A Comprehensive Insight into the Effect of Berberine on Nonalcoholic Fatty Liver Disease (NAFLD): A Systematic Review

Karimi, Arash; Vajdi, Mahdi; Sanaie, Sarvin; Akhlaghi, Shiva; Negari, Aida; Dashti, Farzaneh; Sefidmooye Azar, Pouria

doi:https://doi.org/10.1155/2023/7277060

Journal of Food Biochemistry

On this page

Abstract Introduction Methods Results and Discussion Conclusion Data Availability Conflicts of Interest Authors’ Contributions Acknowledgments References Copyright Related Articles

Review Article | Open Access

Volume 2023 | Article ID 7277060 | https://doi.org/10.1155/2023/7277060

A Comprehensive Insight into the Effect of Berberine on Nonalcoholic Fatty Liver Disease (NAFLD): A Systematic Review

Arash Karimi,¹Mahdi Vajdi,²Sarvin Sanaie,³Shiva Akhlaghi,⁴Aida Negari,⁵Farzaneh Dashti,⁶and Pouria Sefidmooye Azar⁷

Academic Editor: Rafik Balti

Received05 Apr 2023

Revised04 Jun 2023

Accepted12 Jun 2023

Published26 Jun 2023

Abstract

Hepatic dysfunction is primarily caused by nonalcoholic fatty liver disease (NAFLD). Recently, berberine (BBR) has attracted researchers’ interest with its hepatic protective property. A systematic review was conducted to evaluate the effects of BBR and its mechanisms of action in the management of NAFLD and its complications. The guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statements were applied to perform the study. Embase, Web of Science, Google Scholar, Science Direct, PubMed, ProQuest, and Scopus databases were searched up until March 2023. According to the inclusion criteria, finally, 65 studies were entered into the study. The evidence provided in the study revealed that BBR could regulate the development of NAFLD via several mechanisms of action namely lowering body weight, modulating lipid and glucose metabolism, and reducing inflammation and oxidative stress (OS). The current systematic review demonstrated the beneficial effects of BBR on NAFLD and its associated metabolic disorders including dyslipidemia, obesity, and insulin resistance through regulating lipid metabolism, facilitating β-oxidation of fatty acids, and mitigating the accumulation of triglycerides in hepatocytes. These beneficial effects make BBR a potential therapeutic approach and an efficient agent in the management of NAFLD and its related risk factors. There is an insufficient number of clinical trials addressing the effects of BBR in humans, so conducting more human research in the future is recommended.

1. Introduction

Nonalcoholic fatty liver disease (NAFLD), one of the most common health problems globally, is responsible for chronic liver diseases in both developing and developed countries [1, 2]. It is characterized by the abnormal accumulation of triglyceride (TG) and free fatty acids (FFAs) in hepatocytes (more than 5% of liver weight). In addition, NAFLD is known to be associated with metabolic comorbidities namely impaired glucose metabolism, obesity, hyperlipidemia, and insulin resistance (IR) [3]. The wide spectrum of NAFLD varies from simple steatosis to nonalcoholic steatohepatitis (NASH), necroinflammation, cirrhosis, and even hepatocellular carcinoma [3]. In accordance with an estimation, the prevalence of NAFLD is about 25.2% (nearly one billion adult individuals) worldwide [1]. It has been demonstrated that Western dietary patterns, low physical activity, and genetic predisposition play an impressive role in the enlargement of NAFLD [4]. Regarding the hypothesis of the “two-hit,” TG accumulation occurs in the first hit due to some factors namely IR, obesity, diets with higher fats, and absence of physical activity [5]. In the second hit, oxidative stress is caused by excessive fat accumulation, resulting in mitochondrial dysfunction, hepatic cell damage, and further liver cell injury [5].

Although numerous metabolic pathways have been suggested to initiate the development of NAFLD, the exact mechanism remains to be investigated [6]. It has been elucidated that NAFLD emerges from either elevated de novo lipogenesis of FFAs or lipolysis from adipose tissues and hepatic TG disposal. This lipolysis is through the oxidation or secretion of very-low-density lipoprotein (VLDL) particles [7]. Furthermore, insulin resistance and severe inflammation are both implicated in the development of NAFLD through enhancing the expression of lipogenic enzymes namely fatty acid synthetase (FAS) and acetyl-CoA carboxylase 1 (ACC-1) and inhibiting the expression of fatty acid oxidation enzymes including carnitine palmitoyl transferase 1a (CPT1a) [8, 9]. In addition, β-oxidation insufficiency and inflammatory signaling pathways, which stimulate oxidative stress (OS), could induce both IR and liver damage [10]. Several studies have demonstrated that natural compounds such as berberine, rutin, naringin, curcumin, quercetin, epicatechin, and resveratrol, along with healthy lifestyle modifications such as regular physical activity and a healthy diet, can ameliorate NAFLD [11].

Berberine (BBR), a quaternary ammonium salt is quinoline alkaloid with the chemical formula of C₂₀H₁₈NO₄⁺, is a natural composite derived from several plants, especially Berberis vulgaris L, which is from the Berberidaceae family [12]. Previous studies have elucidated numerous pharmacology functions of BBR including antitumor, anticancer, antidiabetic, antioxidative, anti-inflammatory, cardioprotective, antiplatelet aggregation, enhancing immunological functions, decreasing blood lipid levels, Cerebro-protective, antimalaria, and antimicrobial [12]. It has been demonstrated that the hepatic tissues are the major target of BBR since the liver has the highest concentration of BBR metabolites (approximately 70 times as large as its concentration in serum) [13]. Recently, BBR has shown protective effects on hepatic damage, and it has been considered an effective treatment for NAFLD [13]. It has been well-documented that there is a close association between stress oxidative and fatty liver diseases. BBR could prevent reactive oxygen species (ROS) production by suppressing the expression of NADPH oxidase-2 (Nox-2), which is responsible for the cytoplasmic production of ROS [14]. Furthermore, BBR reduces the glucose levels of serum by upregulating the expression of glucose transporter 4 (GLUT4). In a study conducted on a high-fat diet (HFD)-induced NAFLD rat models, BBR ameliorated NAFLD through the regulation of inflammatory responses, which in turn prevented the release of proinflammatory cytokines such as TNF-α and IL-6 [15]. Given the findings of several studies, BBR could exert protective effects on NAFLD and its related complications and could prevent liver damage [12, 15]. Nowadays, there are several drugs and commercial products containing BBR such as coptis chinesis, so it is crucial to assess the potential effects of BBR [16]. Moreover, to our knowledge, no systematic review has ever summarized results on this topic. Therefore, the present study was designed as a comprehensive systematic review of published studies to evaluate the therapeutic effects of this natural compound on NAFLD and its consequent risk factors by elaborating upon the possible mechanisms of BBR’s function.

2. Methods

2.1. Search Approach

The current systematic review was performed concerning the guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statements (Table 1, Electronic Supplementary Material). The study was registered in the PROSPERO (CRD42021277602). A comprehensive search was conducted in Embase, Web of Science, Science Direct, Google Scholar, PubMed, ProQuest, and Scopus, to identify relevant studies up to March 2023. The merger of MeSH and non-MeSH terms were as follows: “berberine” [Mesh], “fatty liver” [Title/Abstract], “nonalcoholic fatty liver disease” [Mesh], “NAFLD” [Mesh], “liver fibrosis” [Title/Abstract], “NASH” [Mesh], “hepatic steatosis” [Title/Abstract], “nonalcoholic steatohepatitis” [Title/Abstract], “insulin resistance” [Title/Abstract], “lipid and glucose metabolism” [Title/Abstract], “diabetes” [Title/Abstract], “T2DM” [Title/Abstract], “oxidative stress” [Mesh], “inflammation” [Mesh], “obesity” [Mesh], “BMI” [Title/Abstract], “fat mass” [Title/Abstract], “dyslipidemia” [Mesh], and “free fatty acids [Title/Abstract].” The search methods in the databases have been supplementary files. The selected studies were limited to English-language articles and those which were published up until March 2023. Moreover, we manually checked all reference lists of eligible studies in order to avoid missing any relevant studies. Finally, all recorded studies found by manual or electronic searches were entered into EndNote software (EndNote X8, Thomson Reuters, New York) for screening.

2.2. Inclusion Criteria

The inclusion criteria of the current study involved the following: (a) available in English-language studies, which were relevant to the current systematic review topic, (b) all clinical trials, animal, and in vitro studies that explored the impacts of BBR supplementation on NAFLD and its consequent disorders, and (c) no extra supplementation must be administered with BBR.

2.3. Exclusion Criteria

The exclusion criteria were based on the following: (a) non-English Language articles, (b) studies with inadequate data, (c) studies that assessed the effects of BBR on diseases other than NAFLD, and studies that examined the effects of a mixture of natural compounds on NAFLD, and (d) review studies, comments, presentation, report, editorial, or books chapters.

2.4. Data Extraction and Quality Assessment

Eligible articles were retrieved using title/abstract by two independent authors, which consequently were assessed based on inclusion criteria. After the exclusion of irrelevant studies, the full text of remained articles was analyzed meticulously for eligibility and extraction of data. The extracted data from each study contained the first author, study location, study design, the subject of the study, duration and follow-up, year of publication, a dose of BBR, and the main conclusion. In cases of disagreement between reviewers, the controversial articles were discussed by researchers and resolved accordingly.

2.5. Risk of Bias Assessment

Two independent researchers (M.V. and P.A.) assessed the risk of bias for selected studies. Furthermore, the Cochrane risk of bias (ROB) was used to evaluate the overall degree of bias for randomized controlled trials. Regarding animal studies, the SYRCLE risk of bias tool was carried out to assess the overall risk of bias. The SYRCLE risk [59] of the bias tool comprises seven domains namely attrition bias, performance bias, detection bias, random sequence generation, reporting bias, allocation concealment, and other bias sources. The quality of the in vitro studies was assessed using the OHAT risk of bias tool [60]. These tools assessed attrition, detection, selection, reporting biases, and performance. It was given a “high risk” score for studies that contained methodological issues liable to affect their results, a “low risk” score for those without methodological issues, and an “unclear risk” score for those with inadequate data.

3. Results and Discussion

3.1. Literature Search

In order to find relevant English studies up to the end of March 2023, two authors independently searched databases. We identified 819 articles from databases (35 from Cochrane, 204 from Scopus, 134 from Embase, 78 from PubMed, 147 from Science Direct, and 221 from the Web of Sciences). The title and abstract of 321 articles remained after eliminating duplicate studies. The topic of the study led to the consideration of 125 studies.) An evaluation of 65 articles found 19 in vitro studies, 41 animal studies, and 5 human studies suitable for inclusion in the present study was conducted. The stages of the study are shown in Figure 1.

3.2. Risk of Bias

The OHAT risk of bias tool was applied to assess the In vitro studies. According to the qualitative assessment, most studies were rated as low risk of bias for the incomplete analysis, similarity of experimental conditions, confidence in the adequate administration of dose or exposure level, exposure characterization, and other bias sources. Almost all of these studies blinding of outcome evaluator were not noted clearly. Methods of allocation of groups were properly described in 65% of the included studies (Figure 2). All 41 animal studies were assessed for risk of bias using SYRCLE’s tool. The qualitative assessment indicated that most studies were rated as low risk of bias for the group similarities at sequence generation category, other sources of bias category, and baseline category, and in most of these studies, blinding of outcome assessor, random outcome assessment, randomization in animal housing, and investigators/caregivers were not reported clearly. Methods of allocation concealment were properly reported in 75% of the included studies. The risk of bios-selective outcome reporting and incomplete outcome data was identified in six (15%) studies and five (12%) studies, respectively (Figure 3). All five studies were randomized, and all of them reported the method of randomization. Methods of allocation concealment were properly described in four of the five included studies. One study was judged to be at high risk of bias which was prone to detection bias. The risk of bias was unclear for the remaining four studies (Figure 4).

This review paper properly addressed the effects of BBR on inflammation, lipid profile, glycemic parameters, obesity, and OS in both human and animal studies. The findings of the current systematic review demonstrated that BBR could attenuate NAFLD and its linked metabolic conditions namely obesity, hyperlipidemia, and insulin resistance. Both animal and human studies have confirmed that BBR can mitigate the inflammatory pathways namely NOD, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and Toll-like receptor 4 (TLR4)/nuclear factor kappa-light-chain (NF-κB) signaling pathways, and stress oxidative by inhibiting the overproduction of ROS [46, 61]. Additionally, nearly all of the studies have shown the potential role of BBR in reducing serum lipids such as TC, LDL-C, TG, and increasing HDL levels [56]. Although, in some studies, berberine did not affect the serum levels of HDL, LDL, TG, TC, and hepatic enzymes, the majority of experiments indicated the beneficial effects of berberine on lipid profile [39, 62]. Of note, berberine can improve glucose metabolism by reducing insulin resistance, fasting blood glucose, and stimulating the uptake of glucose by peripheral tissues. The impact of BBR on body weight, as important comorbidity, was noticeable [51, 63]. In this regard, most studies confirmed the weight-lowering property of berberine [64].

3.3. Beneficial Effects of BBR on NAFLD and Its Related Complications and Mechanisms of Its Action

The mechanisms regarding the BBR function in the management of NAFLD and its related disorders are discussed in three sections obesity, metabolic risk factors, inflammatory parameters, and oxidative stress. The proposed multiple pathways for berberine action are presented in Figures 5 and 6.

3.3.1. Antiobesity Effects of Berberine

There is a positive association between the prevalence of NAFLD and body mass index (BMI) [65]. Therefore, dietary supplements and medications, which are prescribed for weight-lowering purposes, could be administered for the management of NAFLD patients [39, 56]. It is becoming evident that the treatment of obesity, at least slow weight loss, could result in the improvement of liver fibrosis and inflammation, inhibition of fat accumulation, and mitigation of hepatic enzymes [66]. In vitro, In vivo, and human studies have shown that BBR could ameliorate obesity by different mechanisms, for instance, by preventing the expression of genes, which induce the differentiation and propagation of adipocytes, gut microbiota regulation, liver gluconeogenesis, and intestinal permeability [27, 39, 66]. BBR could enhance BAT mass and function, which in turn leads to the amelioration of obesity. Furthermore, in mice models, BBR increased the thermogenesis of BAT and total energy expenditure through BAT proliferation and expression of brown adipogenic genes [32]. BBR could induce the expression of liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs) [18]. PPARs act as molecular sensors of fatty acids and control the metabolism of energy. It also has been indicated that BBR could increase the transcription of AMP-activated protein kinase (AMPK)-P PR domain-containing 16 (RDM16), a regularization of brown/beige adipogenesis, through modulating the active DNA demethylation of PRDM16 the promoter [18, 19, 32]. This might be due to the upregulation of AMPK, and downstream tricarboxylic acid cycle intermediates α-ketoglutarate. Furthermore, BBR could elevate the expression levels of uncoupling protein 1 (UCP1), PRDM16, PPAR-γ in BAT-SVF cells, which decrease FFA [18, 19, 32]. BBR significantly inhibited the expression of activating transcription factor 4 (ATF4), cytochrome P450 2E1 (CYP2E1), and C/EBP homologous protein (CHOP), which are involved in the process of oxidative stress and fatty acid β-oxidation, fatty acid uptake in the live and adipose tissue. Convincing evidence exerted that dysbiosis of the gut microbiota might induce metabolic inflammation via triggering metabolic endotoxemia [47]. It has been shown that BBR could improve obesity and insulin resistance by modulating gut microbiota [47]. In this regard, BBR induces the expression of insulin receptor substrate-1 (IRS-1) and insulin receptor (IRc), which consequently improves insulin resistance and obesity [42]. Another possible mechanism regarding the antiobesity property of BBR is through modulating gene expression, and it has been suggested that BBR suppresses the differentiation of adipocytes via controlling adipogenesis-mediated genes namely PPAR-γ, cAMP-response element-binding (CREB) protein, GATA-2, and GATA-3 [67, 68]. On the other hand, BBR could stimulate thermogenic genes in both BAT and weight adipose tissue (WAT), and UCP1 [32]. Previous studies reported that BBR could exhibit weight-lowering effects by inhibiting the fibrosis of adipose tissue [23]. BBR inhibits polarization and macrophage infiltration in the adipose tissue. In addition, in WAT, BBR could activate AMP-activated protein kinase (AMPK) and suppress the transforming growth factor (TGF)-β (TGF-β1)/Smad3 signaling pathway, which consequently alleviates adipose tissue fibrosis. Therefore, based on the aforementioned findings, it can be concluded that treatment with BBR attenuates obesity, as a vital risk factor for the pathogenesis of NAFLD, and its associated complications.

3.3.2. Effects of Berberine on Metabolic Risk Factors regarding NAFLD

(1) Lipid Metabolism. Compelling evidence has shown that BBR could play a vital role in numerous aspects of lipid hemostasis through different mechanisms. BBR ameliorates cholesterol levels by stimulating the expression of LDL receptors in hepatocytes, which is mediated through the extracellular-signal-regulated kinase (ERK) pathway [25, 41]. Moreover, it has been documented that BBR induces the expression of LDL receptors through both suppressing the proprotein convertase subtilisin/kexin type 9 (PCSK9) LDL receptor pathway and downregulation of hepatocyte nuclear factor 1a (HNF-1a) protein, as a mediator for PCSK9 gene transcription [12, 69, 70]. PCSK9 increases the degradation of LDL receptors by diverting these receptors toward lysosomes [12]. Thus, the cholesterol-lowering effects of BBR might be due to suppressing the PCSK9 pathway [69, 70]. Another possible mechanism of BBR is through triggering the excretion of cholesterol from the liver into the bile, which ultimately leads to a reduction in cholesterol levels [36, 37]. Of note, BBR attenuates dietary cholesterol uptake through the alteration of intestinal absorption in Caco-2 cells by suppressing the expression of acyl-coenzyme A cholesterol acyltransferase (ACAT)-2 and inhibiting micellization of cholesterol in the intestinal lumen [71, 72]. Furthermore, in in vitro studies, BBR reduces intestinal permeability via Caco-2 tight junction monolayer. It is becoming evident that BBR promotes bile acid synthesis from cholesterol by stimulating the expression of mitochondrial sterol 27-hydroxylase and activation of cholesterol 7 alpha-hydroxylase [73, 74]. BBR also could promote fatty acid oxidation and inhibit lipogenesis via AMPK. The 3-hydroxy-3 methyl glutaryl-coenzyme A (HMG)-CoA reductase, a regulatory enzyme in the process of hepatic cholesterol synthesis, could be suppressed by BBR, which in turn reduces the cholesterol levels [8, 17]. The activation of AMPK by BBR inhibits SREBP-1c, which in turn attenuates NAFLD development. Xu et al. [37] reported that supplementation with 300 mg/day resveratrol for 4 weeks resulted in a significant decrease in serum levels of high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG). Also, they showed that BBR leads to suppression of the expression of lipogenesis genes including SCD1, FAS, FAO, sterol regulatory element-binding protein 1 (SREBP-1c), increase in the transcriptional expression of PPARa and CPT-1a in NAFLD rats. In other study, Zhao et al. [8] reported that BBR intake at a dose of 250 mg/kg body weight resulted in a reduction in serum TG and TC levels in NAFLD rats, and they also suggested that BBR might reduce lipid profile by decreasing the expression of protein SREBP-1c and FAS.

(2) Glycemic Parameters. A growing body of evidence demonstrated the glucose-lowering effects of BBR in both clinical trials and animal studies. BBR has been shown to enhance p-IRS levels and ameliorate plasma insulin levels and glucose homeostasis via downregulation of c-Jun N-terminal kinase (JNK) signaling activity, P38 A mitogen-activated protein kinase (MAPK), and upregulation of AMPK [23, 75, 76]. BBR could improve the uptake of glucose by muscle cells via activating glucose transporter type 4 (GLUT-4) translocation, which is consistent with the upregulation of AMPK, an energy sensor that participates in the cellular metabolism by its regulatory activity [23, 75]. Also, the activation of the AMPK can modulate glucose metabolism in liver cells by inhibiting genes responsible for carbohydrate transport solute carrier family 2 member 1 (Slc2a1) and Slc2a4 and glucose metabolisms such as fructose-bisphosphate 1 (FBP1), glucose-6-phosphatase catalytic subunit (G6PC), glucose-6-phosphate dehydrogenase, glycerol-3-phosphate dehydrogenase 1 (GPD1), phosphoenolpyruvate carboxykinase 2, and mitochondrial PCK2, and glycogen synthase kinase 3 beta (GSK3B) [77, 78]. Of interesting, berberine induces Ser/Thr phosphorylation of IRS-1 and increases the phosphorylation of Akt via enhancing the expression of PI3K, which leads to the improvement of hepatic insulin resistance [42]. On the other hand, BBR improves IR by the PPAR-γ pathway [45, 55]. BBR inhibits PTP1B expression by increasing the activity of PKB, PI3K, and GLUT4 and decreasing the expression of GSK-3β and glucose 6-phosphate (G6P). Therefore, it increases the glycogen storage of the liver and reduced insulin resistance [79].

The PPAR and different isoforms of PPARs, particularly PPAR-γ, affect insulin metabolism and decrease the serum cholesterol, which acts as a vital ligand-dependent mediator in the homeostasis enzymes’ expression [80]. BBR could also prohibit the aberrant phosphorylation of IRS-1 and upregulate the downstream protein expression and phosphorylation (p-Akt/Akt, PI3K, and GSK-3β/p-GSK-3β), which in turn leads to the improvement of hepatic insulin signal transduction [42]. In addition, berberine exerted protective effects against hepatic steatosis through the modulation of gut microbe, elevating the serum glucagon-like peptide-1 and neuropeptide Y, and attenuating orexin-A levels, which in turn regulates energy metabolism and reduces the animals’ capacity to uptaking energy from food [36]. BBR has been shown to improve insulin resistance by stimulating the expression of insulin receptor substrate-2 (IRS-2) mRNA, a vital agent in the insulin signaling pathway, in hepatocytes [51]. Of note, BBR decreased the expression of metabolism-related genes like CPT-1a (regulates the oxidation of fatty acids), MTTP (regulates VLDL and LDL levels), and GCK responsible for the modulation of glucose metabolism rate [22]. Teodoro et al. [52] reported that different doses of BBR intake at a dose of 100 mg/kg b.w. improve hepatic insulin signal transduction with the administration of BBR. Orally supplementation of BBR for 4 weeks contributed to the decrease in serum levels of insulin, HbA1c. In another study, 187.5 mg/kg/day BBR for four weeks improved insulin resistance via upregulating mRNA and protein levels of IRS-2 [51]. Thus, it could be concluded that BBR might be a potential therapeutic agent in the treatment of NAFLD due to its beneficial effects on glucose metabolism [56].

(3) Hepatoprotective Effect of Berberine. Several studies indicated that BBR could reduce the serum level of liver enzymes namely ALT and AST, which in turn attenuates liver injury and steatosis [8, 41]. Serum levels of transaminases are the markers of liver steatosis and tissue impairment [81]. Therefore, one of the hepatoprotective effects of BBR might be through the modulation of liver enzymes [41]. For instance, in a study conducted on HFD rat models, 48 hours of BBR supplementation significantly reduced the serum levels of AST and ALT [56]. In other study, Chen et al. [12] investigated the effects of BBR on liver function in experimental NAFLD rats. Rats were orally administered with BBR at a dosage of 100 and 300 mg/kg/day/for 8 weeks. BBR treatment considerably reduced alanine transaminase (ALT) and aspartate transaminase (AST) levels in the liver. In one of the studies, the dose of BBR used varied from 50 to 150 mg/kg/b.w for 4 weeks, resulting in a considerable improvement in the levels of ALT, AST in NAFLD rats [19]. Moreover, 4 weeks of BBR administration at the dosage of 200 mg/kg/day in methionine- and choline-deficient (MCD) mice decreased the plasma levels of hepatic enzymes [22]. BBR could reduce liver damage by decreasing the regulation of NADPH oxidase-2 (NOX2).

3.3.3. Protective Effects of BBR on Inflammation and Stress Oxidative in NAFLD

It has been demonstrated that oxidative stress, mitochondria impairment, and inflammatory signaling pathways could also contribute to the pathogenesis of NAFLD [10]. According to the existing evidence, the serum levels of inflammatory markers are higher in NAFLD patients, while anti-inflammatory mediators have low concentrations. In this regard, BBR could alleviate the NAFLD progression by inhibiting Toll-like receptor 4 (TLR4)/nuclear factor-kappab (NF-κB) signaling pathway [82]. The activated NF-κB, as a result of TLR 4-induced cascade of downstream signals, could lead to the activation of proinflammatory cytokines including IL-6 and TNF-α [8]. Proinflammatory cytokines, including TNF-α, play a vital role in the development of NAFLD by disrupting the insulin signaling pathway resulting in insulin resistance (IR) [82]. In addition, the upregulatory impacts of BBR on AMPK reduce the proinflammatory responses. Yan et al. [45] investigated the effects of oral supplementation of 300 mg of BBR for 6 weeks in HFD-induced NAFLD rats. The findings demonstrated that BBR could prohibit the expression of SREAP-1c, FAS, TLR-4, TRL-9, NLRP3, and ASC in the liver and reduce the expression of IL-1β, TNF-α, IL-8, and IL-6 in the liver; however, it did not affect the expression of PPAR-α. Regarding oxidative stress, BBR supplementation (100 mg/kg) for 4 weeks in 5 mice has been shown to suppress the production of ROS, the expression of TNF-α, and the phosphorylation of NF-κB p65 [18]. Mai et al. [18] evaluated the effects of BBR on inflammation-related pathways in QSG-7701 cells. The results showed that BBR supplementation (10 or 20 mM) to QSG-7701 cells resulted in a reduction in the expression of TNF-α and an increase in the expression of PPAR-α and ACOX1. In other study, Wang et al. [33] investigated the effects of BBR (0–10 μM) in RAW 264.7 cells for 24 hours. They observed that BBR substantially reduced the expression of proinflammatory cytokines, namely, IL-6, MCP-1, TNF-α, and IL-1β. Furthermore, BBR could inhibit the expression of ER stress genes, including ATF4, CHOP, and XBP-1.

C-C motif ligand 19 (CCL19), known as macrophage inflammatory protein-3β (MIP-3β) as well, is expressed by dendritic cells and macrophages and contributes to chronic inflammation [8, 29, 54]. Studies have indicated that BBR promotes the expression of phosphorylated-AMPK (p-AMPK) by suppressing CCL19, which in turn inhibits SREBP-1c [8, 23, 29, 48, 54]. Another possible anti-inflammatory effect of BBR in NAFLD is by inhibiting the NLRP3 inflammasome signaling pathway [28]. Inflammasomes, as a group of multimeric protein complexes, promote the expression of proinflammatory cytokines namely Il-18 and IL-1β by activating caspase-1 during infection, metabolic imbalance, and tissue damage [83]. Several studies have confirmed the effects of NLRP3, as an important inflammasome, on liver injury and hepatic fibrosis. It has been demonstrated that BBR administration could suppress the activation of inflammasomes by affecting the purinergic (P2X7) receptor [28]. It has been demonstrated that BBR may ameliorate nonalcoholic steatohepatitis and hepatoprotective effects by restoring the Treg/Th17 ratio, reducing lipid accumulation, and regulating the chemerin/CMKLR1 signaling pathway to attenuate hepatic inflammation. Oxidative stress is resulting from an imbalance between the cell’s redox environment and antioxidant defenses in human tissues [1, 84]. In NAFLD, the elevated levels of free FFA in the liver promote the production of ROS, mitochondrial dysfunction, and ATP depletion, which leads to oxidative stress [14, 52]. Several possible mechanisms have been proposed for the antioxidant effect of BBR. Antioxidant effects of BBR could be through Sirt 3 activation [36]. Sirt 3 contributes to energy metabolism by regulating the acetylation of mitochondrial enzymes [37]. BBR improves mitochondrial function, particularly at least, through Sirt 3 activation, which consequently reduces the ROS generation [36, 37]. Furthermore, it has been demonstrated that BBR inhibits the over-production of ROS by suppressing the expression of Nox-2 [85]. The NADPH oxidase-2 (Nox-2), one of the NADPH oxidase family members, contributes to the generation of cytoplasmic ROS by generating superoxide in NAFLD patients, which result in hepatic steatosis [85]. In a study by Sun et al. [14], 10 μM of BBR in Huh7 and HepG2 could substantially mitigate the expression of Nox2, Nrf-2, HO-1, and SOD. Of note, the findings of another study by Rafiei et al. [30] demonstrated that BBR (10 μM) had no impact on the expression of iNOS in HepG2.

Of note, BBR inhibits the mitochondrial ROS generation by downregulation of complex I and II in the electron chain. On the other hand, BBR upregulates complex V expression, which indicates that it does not attenuate ATP generation [14].

3.4. Strengths, Limitations, Future Directions, and Knowledge Gaps

The present study has both limitations and strengths. To the best of our knowledge, this is the first systematic review investigating the effects of BBR supplementation and mechanism of action on patients with NAFLD. BBR and metformin have similar effects in controlling hemoglobin a1c levels. They also have similar effects on fasting blood glucose levels and postprandial blood glucose levels [86]. Glucosyl is a BBR supplement. When glucosyl and metformin are taken together, it has an additive effect [87]. This means that hemoglobin a1c, fasting blood glucose, and postprandial glucose levels decrease further. Metformin lowers hemoglobin a1c, but it also lowers body weight. When it comes to BBR and metformin for weight loss, metformin appears to be superior to BBR, also helping to reduce the risk of death from cardiovascular disease [88]. Both metformin and BBR support healthy blood sugar levels. They are similar in terms of their mechanism of action and their effect on the body at the cellular level. Metformin and BBR both increase AMPK enzyme activity [87]. The study reviewed both animal and human studies with sufficient sample sizes. Moreover, the duration of interventions was between 1 hour and 16 weeks, and different doses of BBR supplementation were administered. In spite of its strengths, the main limitation of the study was the heterogeneity of selected studies, which could be due to the variation in doses, study durations, etc. Another notable limitation was entering English publications only. Although several in vitro, in vivo, and animal studies, particularly rat and mouse models, have shown the beneficial effects of BBR on NAFLD, more clinical trials and animal experiments are required, before conducting large-scale endpoint studies. Of note, HFD-induced NAFLD animal models can simulate the mechanisms and pathogenesis of NAFLD in humans, yet there might be different histopathology, which should be confirmed. Due to the administration of various dosages of BBR in experimental studies, the lack of information regarding the required dosage ranges is considerable, which is needed to be elucidated. Moreover, there is a substantial lack of information on the possible side effects of BBR supplementation in both animal and human tissues. For example, Sun 2017, et al. demonstrated that BBR supplementation (200 mg/kg/d in rats and 300 mg/kg/d in mice for 8 weeks) could suppress the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) in hepatic cells. The Nrf-2 is a transcription factor, which is activated in the presence of ROS and promotes the expression of antioxidant enzymes including HO-1 by translocation to the nucleus. As a result, in a bid to identify probable side effects of BBR, further experimental studies are essential. It should be mentioned that due to the heterogeneity of the studies and particularly few available human studies, the current review could not be a meta-analysis study.

3.5. Side Effects

Despite the beneficial effects of BBR against various diseases, in particular NAFLD, some studies have reported the incidence of side effects regarding the administration of BBR at higher doses [38]. It seems that BBR at low doses is safe for both the animal and human body. Also, taking high doses of BBR may cause digestive disorders such as diarrhea, constipation, abdominal pain, and bloating [89, 90]. Evidence has suggested that BBR is well tolerated at the dosage of 0.3 g/daily in combination therapy [91].

4. Conclusion

The present systematic review exerted the beneficial effects of BBR on NAFLD and its associated metabolic disorders including dyslipidemia, obesity, and insulin resistance. The results of the study have demonstrated the noteworthy antihyperlipidemic effects of BBR, which are attributed to its ability to regulate lipid metabolism, facilitate the β-oxidation of fatty acids, and mitigate the accumulation of triglycerides in hepatocytes. In addition, it has been observed that BBR has a positive impact on NAFLD through the regulation of inflammatory signaling pathways, inhibition of oxidative stress, and reduction in the excessive production of cytoplasmic and mitochondrial ROS. The therapeutic properties of BBR in NAFLD and its associated complications have been observed in various studies, indicating its potential as a potent medication for NAFLD management.

Data Availability

All data generated or analyzed during this study are included in this published article.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors’ Contributions

AK, IN, VA, SS, PSMA, and FD developed the first hypothesis of the study and searched the data, and both authors assessed and extracted data. AK, PSMA, and MV wrote the draft of the manuscript. AK and PSMA contributed to data collection; MV provided advice and consultation; AK contributed to the final revision of the manuscript.

Acknowledgments

The authors would like to thank the Tabriz University of Medical Sciences for its support.

References

F. Kooshki, F. Moradi, A. Karimi et al., “Chromium picolinate balances the metabolic and clinical markers in nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled trial,” European Journal of Gastroenterology and Hepatology, vol. 33, no. 10, pp. 1298–1306, 2020.
View at: Publisher Site | Google Scholar
S. Pourreza, P. S. Azar, S. Sanaie et al., “Therapeutic effects and mechanisms of action of garlic (allium sativum) on nonalcoholic fatty liver disease: a comprehensive systematic literature review,” Evidence-based Complementary and Alternative Medicine, vol. 2022, pp. 1–15, 2022.
View at: Publisher Site | Google Scholar
Y. Sumida and M. Yoneda, “Current and future pharmacological therapies for NAFLD/NASH,” Journal of Gastroenterology, vol. 53, no. 3, pp. 362–376, 2018.
View at: Publisher Site | Google Scholar
H. M. Al-Dayyat, Y. M. Rayyan, and R. F. Tayyem, “Non-alcoholic fatty liver disease and associated dietary and lifestyle risk factors,” Diabetes and Metabolic Syndrome: Clinical Research Reviews, vol. 12, no. 4, pp. 569–575, 2018.
View at: Publisher Site | Google Scholar
Y.-L. Fang, H. Chen, C.-L. Wang, and L. Liang, “Pathogenesis of non-alcoholic fatty liver disease in children and adolescence: from “two hit theory” to “multiple hit model”,” World Journal of Gastroenterology, vol. 24, no. 27, pp. 2974–2983, 2018.
View at: Publisher Site | Google Scholar
S.-S. Lei, N.-Y. Zhang, F.-C. Zhou et al., “Dendrobium officinale regulates fatty acid metabolism to ameliorate liver lipid accumulation in NAFLD mice,” Evidence-based Complementary and Alternative Medicine, vol. 2021, Article ID 6689727, pp. 2021–2112, 2021.
View at: Publisher Site | Google Scholar
X. Zhang, C. Huang, X. Li et al., “HFD and HFD-provoked hepatic hypoxia act as reciprocal causation for NAFLD via HIF-independent signaling,” BMC Gastroenterology, vol. 20, pp. 366–369, 2020.
View at: Publisher Site | Google Scholar
J. Zhao, Y. Wang, X. Wu et al., “Inhibition of CCL19 benefits non-alcoholic fatty liver disease by inhibiting TLR4/NF-κB-p65 signaling,” Molecular Medicine Reports, vol. 18, no. 5, pp. 4635–4642, 2018.
View at: Publisher Site | Google Scholar
H. F. Sakr, A. M. Hussein, E. A. Eid, and M. AlKhateeb, “Possible mechanisms underlying fatty liver in a rat model of male hypogonadism: a protective role for testosterone,” Steroids, vol. 135, pp. 21–30, 2018.
View at: Publisher Site | Google Scholar
P. Farzanegi, A. Dana, Z. Ebrahimpoor, M. Asadi, and M. A. Azarbayjani, “Mechanisms of beneficial effects of exercise training on non-alcoholic fatty liver disease (NAFLD): roles of oxidative stress and inflammation,” European Journal of Sport Science, vol. 19, no. 7, pp. 994–1003, 2019.
View at: Publisher Site | Google Scholar
K. Jakubczyk, K. Skonieczna-Żydecka, J. Kałduńska, E. Stachowska, I. Gutowska, and K. Janda, “Effects of resveratrol supplementation in patients with non-alcoholic fatty liver disease—a meta-analysis,” Nutrients, vol. 12, no. 8, p. 2435, 2020.
View at: Publisher Site | Google Scholar
P. Chen, Y. Li, and L. Xiao, “Berberine ameliorates nonalcoholic fatty liver disease by decreasing the liver lipid content via reversing the abnormal expression of MTTP and LDLR,” Experimental and Therapeutic Medicine, vol. 22, no. 4, pp. 1–18, 2021.
View at: Publisher Site | Google Scholar
Z. Lu, B. He, Z. Chen, M. Yan, and L. Wu, “Anti-inflammatory activity of berberine in non-alcoholic fatty liver disease via the Angptl2 pathway,” BMC Immunology, vol. 21, pp. 28-29, 2020.
View at: Publisher Site | Google Scholar
Y. Sun, X. Yuan, F. Zhang et al., “Berberine ameliorates fatty acid-induced oxidative stress in human hepatoma cells,” Scientific Reports, vol. 7, p. 11340, 2017.
View at: Publisher Site | Google Scholar
Y. Wang, S. Cui, J. Zheng, Y. Li, P. Li, and H. Hou, “Berberine ameliorates intestinal mucosal barrier dysfunction in nonalcoholic fatty liver disease (NAFLD) rats,” Journal of King Saud University Science, vol. 32, no. 5, pp. 2534–2539, 2020.
View at: Publisher Site | Google Scholar
Y. Jin, D. B. Khadka, and W.-J. Cho, “Pharmacological effects of berberine and its derivatives: a patent update,” Expert Opinion on Therapeutic Patents, vol. 26, no. 2, pp. 229–243, 2016.
View at: Publisher Site | Google Scholar
X. Zhu, H. Bian, L. Wang et al., “Berberine attenuates nonalcoholic hepatic steatosis through the AMPK-SREBP-1c-SCD1 pathway,” Free Radical Biology and Medicine, vol. 141, pp. 192–204, 2019.
View at: Publisher Site | Google Scholar
W. Mai, Y. Xu, J. Xu et al., “Berberine inhibits Nod-like receptor family pyrin domain containing 3 inflammasome activation and pyroptosis in nonalcoholic steatohepatitis via the ROS/TXNIP axis,” Frontiers in Pharmacology, vol. 11, p. 185, 2020.
View at: Publisher Site | Google Scholar
Y. Zhang, J. Wen, D. Liu et al., “Demethylenetetrahydroberberine alleviates nonalcoholic fatty liver disease by inhibiting the NLRP3 inflammasome and oxidative stress in mice,” Life Sciences, vol. 281, Article ID 119778, 2021.
View at: Publisher Site | Google Scholar
Y. Liu and Z. Zhang, “Effect of berberine on a cellular model of non-alcoholic fatty liver disease,” International Journal of Clinical and Experimental Medicine, vol. 10, pp. 16360–16366, 2017.
View at: Google Scholar
C. H. Li, S. C. Tang, C. H. Wong, Y. Wang, J. D. Jiang, and Y. Chen, “Berberine induces miR-373 expression in hepatocytes to inactivate hepatic steatosis associated AKT-S6 kinase pathway,” European Journal of Pharmacology, vol. 825, pp. 107–118, 2018.
View at: Publisher Site | Google Scholar
H. Liang and Y. Wang, “Berberine alleviates hepatic lipid accumulation by increasing ABCA1 through the protein kinase C δ pathway,” Biochemical and Biophysical Research Communications, vol. 498, no. 3, pp. 473–480, 2018.
View at: Publisher Site | Google Scholar
T. Guo, S.-L. Woo, X. Guo et al., “Berberine ameliorates hepatic steatosis and suppresses liver and adipose tissue inflammation in mice with diet-induced obesity,” Scientific Reports, vol. 6, p. 22612, 2016.
View at: Publisher Site | Google Scholar
G. Xuzhu, M. Komai-Koma, B. P. Leung et al., “Resveratrol modulates murine collagen-induced arthritis by inhibiting Th17 and B-cell function,” Annals of the Rheumatic Diseases, vol. 71, no. 1, pp. 129–135, 2012.
View at: Publisher Site | Google Scholar
Z. Zhang, B. Li, X. Meng et al., “Berberine prevents progression from hepatic steatosis to steatohepatitis and fibrosis by reducing endoplasmic reticulum stress,” Scientific Reports, vol. 6, pp. 1–13, 2016.
View at: Publisher Site | Google Scholar
M. Y. Shan, Y. Dai, X. D. Ren et al., “Berberine mitigates nonalcoholic hepatic steatosis by downregulating SIRT1-FoxO1-SREBP2 pathway for cholesterol synthesis,” Journal of Integrative Medicine, vol. 19, no. 6, pp. 545–554, 2021.
View at: Publisher Site | Google Scholar
X. Yuan, J. Wang, X. Tang, Y. Li, P. Xia, and X. Gao, “Berberine ameliorates nonalcoholic fatty liver disease by a global modulation of hepatic mRNA and lncRNA expression profiles,” Journal of Translational Medicine, vol. 13, pp. 24–11, 2015.
View at: Publisher Site | Google Scholar
E. Vivoli, A. Cappon, S. Milani et al., “NLRP3 inflammasome as a target of berberine in experimental murine liver injury: interference with P2X7 signalling,” Clinical Science, vol. 130, no. 20, pp. 1793–1806, 2016.
View at: Publisher Site | Google Scholar
H. Rafiei, K. Omidian, and B. Bandy, “Comparison of dietary polyphenols for protection against molecular mechanisms underlying nonalcoholic fatty liver disease in a cell model of steatosis,” Molecular Nutrition and Food Research, vol. 61, no. 9, Article ID 1600781, 2017.
View at: Publisher Site | Google Scholar
H. Rafiei, K. Omidian, and B. Bandy, “Protection by different classes of dietary polyphenols against palmitic acid-induced steatosis, nitro-oxidative stress and endoplasmic reticulum stress in HepG2 hepatocytes,” Journal of Functional Foods, vol. 44, pp. 173–182, 2018.
View at: Publisher Site | Google Scholar
X. Qiang, L. Xu, M. Zhang et al., “Demethyleneberberine attenuates non-alcoholic fatty liver disease with activation of AMPK and inhibition of oxidative stress,” Biochemical and Biophysical Research Communications, vol. 472, no. 4, pp. 603–609, 2016.
View at: Publisher Site | Google Scholar
L. Wu, M. Xia, Y. Duan et al., “Berberine promotes the recruitment and activation of brown adipose tissue in mice and humans,” Cell Death and Disease, vol. 10, no. 6, p. 468, 2019.
View at: Publisher Site | Google Scholar
Y. Wang, X. Zhou, D. Zhao et al., “Berberine inhibits free fatty acid and LPS-induced inflammation via modulating ER stress response in macrophages and hepatocytes,” PLoS One, vol. 15, no. 5, Article ID e0232630, 2020.
View at: Publisher Site | Google Scholar
S. Yang, S. Cao, C. Li et al., “Berberrubine, a main metabolite of berberine, alleviates non-alcoholic fatty liver disease via modulating glucose and lipid metabolism and restoring gut microbiota,” Frontiers in Pharmacology, vol. 13, Article ID 913378, 2022.
View at: Publisher Site | Google Scholar
Z. Lu, F. Lu, L. Wu, B. He, Z. Chen, and M. Yan, “Berberine attenuates non-alcoholic steatohepatitis by regulating chemerin/CMKLR1 signalling pathway and Treg/Th17 ratio,” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 394, no. 2, pp. 383–390, 2021.
View at: Publisher Site | Google Scholar
Y. P. Zhang, Y. J. Deng, K. R. Tang et al., “Berberine ameliorates high-fat diet-induced non-alcoholic fatty liver disease in rats via activation of SIRT3/AMPK/ACC pathway,” Current medical science, vol. 39, no. 1, pp. 37–43, 2019.
View at: Publisher Site | Google Scholar
X. Xu, X.-P. Zhu, J.-Y. Bai et al., “Berberine alleviates nonalcoholic fatty liver induced by a high‐fat diet in mice by activating SIRT3,” The FASEB Journal, vol. 33, no. 6, pp. 7289–7300, 2019.
View at: Publisher Site | Google Scholar
Y. Wang, J. Zheng, H. Hou et al., “Effects of berberine on intestinal flora of Non-alcoholic fatty liver induced by High-fat diet through 16S rRNA gene segmentation,” Journal of King Saud University Science, vol. 32, no. 5, pp. 2603–2609, 2020.
View at: Publisher Site | Google Scholar
L. Zhao, Z. Cang, H. Sun, X. Nie, N. Wang, and Y. Lu, “Berberine improves glucogenesis and lipid metabolism in nonalcoholic fatty liver disease,” BMC Endocrine Disorders, vol. 17, pp. 13–18, 2017.
View at: Publisher Site | Google Scholar
J. Yang, X. J. Ma, L. Li et al., “Berberine ameliorates non-alcoholic steatohepatitis in ApoE-/-mice,” Experimental and Therapeutic Medicine, vol. 14, no. 5, pp. 4134–4140, 2017.
View at: Publisher Site | Google Scholar
S. Mehrdoost, P. Yaghmaei, H. Jafary, and A. Ebrahim-Habibi, “The therapeutic effects of berberine plus sitagliptin in a rat model of fatty liver disease,” Iranian journal of basic medical sciences, vol. 24, p. 451, 2021.
View at: Google Scholar
Q.-P. Li, Y.-X. Dou, Z.-W. Huang et al., “Therapeutic effect of oxyberberine on obese non-alcoholic fatty liver disease rats,” Phytomedicine, vol. 85, Article ID 153550, 2021.
View at: Publisher Site | Google Scholar
Y. Wang, S. Lv, T. Shen et al., “Qinghua Fang inhibits high-fat diet-induced non-alcoholic fatty liver disease by modulating gut microbiota,” Annals of Palliative Medicine, vol. 10, no. 3, pp. 3219–3234, 2021.
View at: Publisher Site | Google Scholar
Y. J. Choi, K. Y. Lee, S. H. Jung et al., “Activation of AMPK by berberine induces hepatic lipid accumulation by upregulation of fatty acid translocase CD36 in mice,” Toxicology and Applied Pharmacology, vol. 316, pp. 74–82, 2017.
View at: Publisher Site | Google Scholar
Y. Yan, C. Liu, S. Zhao et al., “Probiotic Bifidobacterium lactis V9 attenuates hepatic steatosis and inflammation in rats with non-alcoholic fatty liver disease,” AMB Express, vol. 10, no. 1, p. 101, 2020.
View at: Publisher Site | Google Scholar
L. Wang, Z. Jia, B. Wang, and B. Zhang, “Berberine inhibits liver damage in rats with non-alcoholic fatty liver disease by regulating TLR4/MyD88/NF-κB pathway,” Turkish Journal of Gastroenterology, vol. 31, no. 12, pp. 902–909, 2021.
View at: Publisher Site | Google Scholar
Y. Cao, Q. Pan, F. Shen, G.-Y. Chen, L.-M. Xu, and J.-G. Fan, “Modulation of gut microbiota by berberine improves steatohepatitis in high-fat diet-fed BALB/C mice,” Archives of Iranian Medicine, vol. 19, 2016.
View at: Google Scholar
Y. Luo, G. Tian, Z. Zhuang et al., “Berberine prevents non-alcoholic steatohepatitis-derived hepatocellular carcinoma by inhibiting inflammation and angiogenesis in mice,” American Journal of Tourism Research, vol. 11, no. 5, pp. 2668–2682, 2019.
View at: Google Scholar
Y. Zhang, X. Chang, X. Song et al., “Berberine reverses abnormal expression of L-type pyruvate kinase by DNA demethylation and histone acetylation in the livers of the non-alcoholic fatty disease rat,” International Journal of Clinical and Experimental Medicine, vol. 8, no. 5, pp. 7535–7543, 2015.
View at: Google Scholar
W. W. Feng, S. Y. Kuang, C. Tu et al., “Natural products berberine and curcumin exhibited better ameliorative effects on rats with non-alcohol fatty liver disease than lovastatin,” Biomedicine and Pharmacotherapy, vol. 99, pp. 325–333, 2018.
View at: Publisher Site | Google Scholar
L.-J. Xing, L. Zhang, T. Liu, Y.-Q. Hua, P.-Y. Zheng, and G. Ji, “Berberine reducing insulin resistance by up-regulating IRS-2 mRNA expression in nonalcoholic fatty liver disease (NAFLD) rat liver,” European Journal of Pharmacology, vol. 668, no. 3, pp. 467–471, 2011.
View at: Publisher Site | Google Scholar
J. S. Teodoro, F. V. Duarte, A. P. Gomes et al., “Berberine reverts hepatic mitochondrial dysfunction in high-fat fed rats: a possible role for SirT3 activation,” Mitochondrion, vol. 13, no. 6, pp. 637–646, 2013.
View at: Publisher Site | Google Scholar
X. Chang, Z. Wang, J. Zhang et al., “Lipid profiling of the therapeutic effects of berberine in patients with nonalcoholic fatty liver disease,” Journal of Translational Medicine, vol. 14, pp. 266–311, 2016.
View at: Publisher Site | Google Scholar
Q. H. Yang, S. P. Hu, Y. P. Zhang et al., “Effect of berberine on expressions of uncoupling protein-2 mRNA and protein in hepatic tissue of non-alcoholic fatty liver disease in rats,” Chinese Journal of Integrative Medicine, vol. 17, no. 3, pp. 205–211, 2011.
View at: Publisher Site | Google Scholar
S. M. M. Ragab, S. K. Abd Elghaffar, T. H. El-Metwally, G. Badr, M. H. Mahmoud, and H. M. Omar, “Effect of a high fat, high sucrose diet on the promotion of non-alcoholic fatty liver disease in male rats: the ameliorative role of three natural compounds,” Lipids in Health and Disease, vol. 14, no. 1, p. 83, 2015.
View at: Publisher Site | Google Scholar
H.-M. Yan, M.-F. Xia, Y. Wang et al., “Efficacy of berberine in patients with non-alcoholic fatty liver disease,” PLoS One, vol. 10, no. 8, Article ID e0134172, 2015.
View at: Publisher Site | Google Scholar
S. A. Harrison, N. Gunn, G. W. Neff et al., “A phase 2, proof of concept, randomised controlled trial of berberine ursodeoxycholate in patients with presumed non-alcoholic steatohepatitis and type 2 diabetes,” Nature Communications, vol. 12, no. 1, p. 5503, 2021.
View at: Publisher Site | Google Scholar
L. Nejati, A. Movahedi, G. Salari, R. Moeineddin, and P. Nejati, “The effect of berberine on lipid profile, liver enzymes, and fasting blood glucose in patients with non-alcoholic fatty liver disease (NAFLD): a randomized controlled trial,” Medical Journal of the Islamic Republic of Iran, vol. 36, p. 39, 2022.
View at: Publisher Site | Google Scholar
C. R. Hooijmans, M. M. Rovers, R. de Vries, M. Leenaars, M. Ritskes-Hoitinga, and M. W. Langendam, “SYRCLE’s risk of bias tool for animal studies,” BMC Medical Research Methodology, vol. 14, pp. 43–49, 2014.
View at: Publisher Site | Google Scholar
A. Rooney, Extending a Risk-Of-Bias Approach to Address in Vitro Studies, National Toxicology Program Office of Health Assessment and Translation, Washington, USA, 2015.
A. M. Gendy, M. R. Elnagar, M. M. Allam et al., “Berberine-loaded nanostructured lipid carriers mitigate warm hepatic ischemia/reperfusion-induced lesion through modulation of HMGB1/TLR4/NF-κB signaling and autophagy,” Biomedicine and Pharmacotherapy, vol. 145, Article ID 112122, 2022.
View at: Publisher Site | Google Scholar
X. Chang, H. Yan, J. Fei et al., “Berberine reduces methylation of the MTTP promoter and alleviates fatty liver induced by a high-fat diet in rats,” The Journal of Lipid Research, vol. 51, no. 9, pp. 2504–2515, 2010.
View at: Publisher Site | Google Scholar
X. Wei, C. Wang, S. Hao, H. Song, and L. Yang, “The Therapeutic Effect of Berberine in the Treatment of Nonalcoholic Fatty Liver Disease: A Meta-Analysis,” Evidence-based Complementary and Alternative Medicine, vol. 2016, Article ID 3593951, 2016.
View at: Publisher Site | Google Scholar
X. Wan, X. Chen, L. Liu et al., “Berberine ameliorates chronic kidney injury caused by atherosclerotic renovascular disease through the suppression of NFκB signaling pathway in rats,” PLoS One, vol. 8, no. 3, Article ID e59794, 2013.
View at: Publisher Site | Google Scholar
T. S. Church, J. L. Kuk, R. Ross, E. L. Priest, E. Biltoff, and S. N. Blair, “Association of cardiorespiratory fitness, body mass index, and waist circumference to nonalcoholic fatty liver disease,” Gastroenterology, vol. 130, no. 7, pp. 2023–2030, 2006.
View at: Publisher Site | Google Scholar
D. Li, J. Zheng, Y. Hu et al., “Amelioration of intestinal barrier dysfunction by berberine in the treatment of nonalcoholic fatty liver disease in rats,” Pharmacognosy Magazine, vol. 13, no. 52, p. 677, 2017.
View at: Publisher Site | Google Scholar
K.-L. Lu, L.-N. Wang, D.-D. Zhang, W.-B. Liu, and W.-N. Xu, “Berberine attenuates oxidative stress and hepatocytes apoptosis via protecting mitochondria in blunt snout bream Megalobrama amblycephala fed high-fat diets,” Fish Physiology and Biochemistry, vol. 43, no. 1, pp. 65–76, 2017.
View at: Publisher Site | Google Scholar
M. Imenshahidi and H. Hosseinzadeh, “Berberis vulgaris and berberine: an update review,” Phytotherapy Research, vol. 30, no. 11, pp. 1745–1764, 2016.
View at: Publisher Site | Google Scholar
C. Li, Z. Hu, W. Zhang et al., “Regulation of cholesterol homeostasis by a novel long non-coding RNA LASER,” Scientific Reports, vol. 9, p. 7693, 2019.
View at: Publisher Site | Google Scholar
S. Bansod, M. A. Saifi, and C. Godugu, “Molecular Updates on Berberine in Liver Diseases: Bench to Bedside,” Phytotherapy Research, vol. 35, no. 10, 2021.
View at: Google Scholar
S. Guo, L. Li, and H. Yin, “Cholesterol homeostasis and liver X receptor (LXR) in atherosclerosis,” Drug Targets, vol. 18, no. 1, pp. 27–33, 2018.
View at: Publisher Site | Google Scholar
Z. Ilyas, S. Perna, S. Al-Thawadi et al., “The effect of Berberine on weight loss in order to prevent obesity: a systematic review,” Biomedicine and Pharmacotherapy, vol. 127, Article ID 110137, 2020.
View at: Publisher Site | Google Scholar
B. Cao, R. B. Sun, G. Yan, G. Y. Yang, J. Y. Aa, and J. Li, “Berberine reverses LPS-induced repression of CYP7A1 through an anti-inflammatory effect,” Chinese Herbal Medicines, vol. 11, no. 3, pp. 292–298, 2019.
View at: Publisher Site | Google Scholar
A. Fatahian, S. M. Haftcheshmeh, S. Azhdari, H. K. Farshchi, B. Nikfar, and A. A. Momtazi-Borojeni, “Promising anti-atherosclerotic effect of berberine: evidence from in vitro, in vivo, and clinical studies,” Reviews of Physiology, Biochemistry and Pharmacology, vol. 178, pp. 83–110, 2020.
View at: Publisher Site | Google Scholar
K. Chen, G. Li, F. Geng et al., “Berberine reduces ischemia/reperfusion-induced myocardial apoptosis via activating AMPK and PI3K-Akt signaling in diabetic rats,” Apoptosis, vol. 19, no. 6, pp. 946–957, 2014.
View at: Publisher Site | Google Scholar
D. S. Zhang, X. H. Bai, Y. J. Yao, D. Z. Mu, and J. Chen, “Effect of Berberine on the Insulin Resistance and TLR4/IKKbeta/NF-kappaB Signaling Pathways in Skeletal Muscle of Obese Rats with Insulin Resistance], Sichuan da xue xue bao,” Medical science edition, vol. 46, Yi xue ban = Journal of Sichuan University, 2015.
View at: Google Scholar
K. Hadova, L. Mesarosova, E. Kralova, G. Doka, P. Krenek, and J. Klimas, “The tyrosine kinase inhibitor crizotinib influences blood glucose and mRNA expression of GLUT4 and PPARs in the heart of rats with experimental diabetes,” Canadian Journal of Physiology and Pharmacology, vol. 99, no. 6, pp. 635–643, 2021.
View at: Publisher Site | Google Scholar
Y. Ge, Y. Zhang, R. Li, W. Chen, Y. Li, and G. Chen, “Berberine regulated Gck, G6pc, Pck1 and Srebp-1c expression and activated AMP-activated protein kinase in primary rat hepatocytes,” International Journal of Biological Sciences, vol. 7, no. 5, pp. 673–684, 2011.
View at: Publisher Site | Google Scholar
C. Chen, Y. Zhang, and C. Huang, “Berberine inhibits PTP1B activity and mimics insulin action,” Biochemical and Biophysical Research Communications, vol. 397, no. 3, pp. 543–547, 2010.
View at: Publisher Site | Google Scholar
V. Bhatia and P. Viswanathan, “Insulin resistance and PPAR insulin sensitizers,” Current Opinion in Investigational Drugs, (London, England: 2000), vol. 7, pp. 891–897, 2006.
View at: Google Scholar
R. K. Schindhelm, M. Diamant, J. M. Dekker, M. E. Tushuizen, T. Teerlink, and R. J. Heine, “Alanine aminotransferase as a marker of non-alcoholic fatty liver disease in relation to type 2 diabetes mellitus and cardiovascular disease,” Diabetes/metabolism research and reviews, vol. 22, no. 6, pp. 437–443, 2006.
View at: Publisher Site | Google Scholar
M. Asrih and F. R. Jornayvaz, “Inflammation as a potential link between nonalcoholic fatty liver disease and insulin resistance,” Journal of Endocrinology, vol. 218, no. 3, pp. R25–R36, 2013.
View at: Publisher Site | Google Scholar
A. Karimi, R. Ghodsi, F. Kooshki, M. Karimi, V. Asghariazar, and A. Tarighat‐Esfanjani, “Therapeutic effects of curcumin on sepsis and mechanisms of action: a systematic review of preclinical studies,” Phytotherapy Research, vol. 33, no. 11, pp. 2798–2820, 2019.
View at: Publisher Site | Google Scholar
A. Gonzalez, C. Huerta-Salgado, J. Orozco-Aguilar et al., “Role of oxidative stress in hepatic and extrahepatic dysfunctions during nonalcoholic fatty liver disease (NAFLD),” Oxidative Medicine and Cellular Longevity, vol. 2020, 16 pages, 2020.
View at: Publisher Site | Google Scholar
K. Bedard and K.-H. Krause, “The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology,” Physiological Reviews, vol. 87, no. 1, pp. 245–313, 2007.
View at: Publisher Site | Google Scholar
J. Yin, H. Xing, and J. Ye, “Efficacy of berberine in patients with type 2 diabetes mellitus,” Metabolism, vol. 57, no. 5, pp. 712–717, 2008.
View at: Publisher Site | Google Scholar
H. Wang, C. Zhu, Y. Ying, L. Luo, D. Huang, and Z. Luo, “Metformin and berberine, two versatile drugs in treatment of common metabolic diseases,” Oncotarget, vol. 9, no. 11, pp. 10135–10146, 2018.
View at: Publisher Site | Google Scholar
L. Wang, D. Liu, G. Wei, and H. Ge, “Berberine and metformin in the treatment of type 2 diabetes mellitus: a systemic review and meta-analysis of randomized clinical trials,” vol. 13, no. 11, pp. 1314–1329, 2021.
View at: Publisher Site | Google Scholar
F. Di Pierro, A. Bertuccioli, R. Giuberti, M. Saponara, and L. Ivaldi, “Role of a berberine-based nutritional supplement in reducing diarrhea in subjects with functional gastrointestinal disorders,” Minerva Gastroenterologica e Dietologica, vol. 66, no. 1, pp. 29–34, 2020.
View at: Publisher Site | Google Scholar
L. Li, H. Cui, T. Li et al., “Synergistic effect of berberine-based Chinese medicine assembled nanostructures on diarrhea-predominant irritable bowel syndrome in vivo,” Frontiers in Pharmacology, vol. 11, p. 1210, 2020.
View at: Publisher Site | Google Scholar
X. Xu, H. Yi, J. Wu et al., “Therapeutic effect of berberine on metabolic diseases: both pharmacological data and clinical evidence,” Biomedicine and Pharmacotherapy, vol. 133, Article ID 110984, 2021.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2023 Arash Karimi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

1305

Downloads

269

Citations