| | Reference | Study design | Number and type of subjects | Dosage and type of administration | Study duration | Main results |
| | In vitro studies | | [17] | In vitro | HepG2 and AML12 cells exposed to high glucose and palmitic acid | 20 μM | 24 h | Reduction in hepatic TG accumulation and the expression of hepatic SCD1 and other TG synthesis-related genes; promotion of the phosphorylation of AMPK and SREBP-1c | | [18] | In vitro | QSG-7701 cells | 10 or 20 mM | 24 h | Inhibition of the expression levels of ROS, MDA, TNF-α, NLRP3, NLRP3, caspase 1, GSDMD, TXNIP, SLC27A1, α-SMA, TGF-β1, FABP1, CYP2E1, ATF-4, CHOP PPAR-γ TLR4, p-NF-κB/NF-κB, and p-I-κB/I-κB; increase in the expression levels of PPAR-α and ACOX1 | | [19] | In vitro | L02 cell | 0, 5, and 15 μM | 24 h | Decrease in the mRNA levels of genes related to lipogeneses such as NLRP3, CYP2E1, ATF-4, and CHOP in L02 cell; increase in the expression levels of AMPK; decrease in MDA and LDH in L02 cell; no effect on the phosphorylation AMPKin H4IIE cells | | [20] | In vitro | HepG2 cells induced by oleic acid (OA) | 0, 0.0, 0.1, and 1 μM | 24 h | Decrease in the fat overload and TG content in OA-induced HepG2 cells; increase in the mRNA of FXR; reduction in the mRNA of SREBP-1c and FAS in a dose-dependent manner | | [21] | In vitro | MIHA and HepG2 cells | 0, 10, and 20 μM | 24 h | Upregulating the EGR1 level which functioned to transactivate miR-373 expression in MIHA and HepG2 cells. Subsequently, miR-373 depleted its target gene AKT serine/threonine kinase 1 (AKT1) mRNA level, which led to the inhibition of the AKT-mTOR-S6K signaling pathway in hepatocytes that were critical in the development of hepatosteatosis | | [22] | In vitro | QSG-7701 cells | 0, 10, and 20 μM | 24 h | Decrease in the phosphorylation of ABCA1 serine residues and PKCd Tyr 311 | | [23] | In vitro | H4IIE cells | 10, 25, and 50 μM | 24 h | Reduction in the phosphorylation state of JNK1 in hepatoma H4IIE cells, the mRNA levels of genes related to lipogeneses such as ACC, FAS, CPT1a, jnk1, and SREBP1c; increase in the expression levels of AMPK; decrease in IL-6, IL-1β, and TNF-α in H4IIE cells | | BBR did not significantly increase the phosphorylation AMPKin H4IIE cells | | [24] | In vitro | Human hepatoma cell line, HepG2 | 0, 1, 10, and 25 μM | 24 h | Activation of AMPK induced the phosphorylation of extracellular-signal-regulated kinases 1/2 (ERK1/2) and subsequently induced CCAAT/enhancer-binding protein β (C/EBPβ) binding to the C/EBP-response element in the CD36 promoter in hepatocytes | | [25] | In vitro | HepG2 and FAO | 5 μM | 24 h | Suppression of the mRNA expression of phospho-PERK, phospho-eIF2α, ATF6, and SREBP-1c; reduction in cellular TG in oleate acid/palmitate acid (OA/PA)-induced excessive lipid accumulation in cultured HepG2, FAO, and primary hepatocytes | | [26] | In vitro | HepG2 cell | 1, 5, 10 μM | 24 h | BBR significantly decreases TC SREBP2 and 3-hydroxy 3-methylglutaryl-CoA reductase levels | | BBR significantly increases mRNA and protein levels of SIRT1, as well as higher acetyl-FoxO1 protein level compared to the FFA-only group | | [27] | In vitro | Huh7 | 10 μM | 24 h | Reduction in the expression of MRAK052686 and Nrf2 was completely reversed by BBR treatment, suggesting a new mechanism accounting for the therapeutic effect of BBR | | [28] | In vitro | RAW264.7 | 10 μM | 24 h | Inflammasome caspase 1, pannexin-1. Limiting the activation of the purinergic receptor P2X7, involved in the late phases of NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome. Upon P2X7 knockdown, the ability of BRB to block LPS-induced secretion of IL-1β was lost | | [14] | In vitro | Huh7 and HepG2 | 10 μM | 24 h | Suppression of the expression levels of Nox2, complex I, II, and III, the expression levels of Nrf-2, HO-1, and SOD; decrease in mitochondrial-derived ROS production induced by FFA | | [29] | In vitro | HepG2 | — | 24 h | No significant effect on Mn-SOD, and UCP2 expressions | | [30] | In vitro | HepG2 | 10 μM | 24 h | No significant effect on mRNA expression levels of iNOS | | [31] | In vitro | HepG2 | 10 or 20 mM | 24 h | Activating AMPK by increasing 3 its phosphorylation | | [32] | In vitro | BAT-SVF cells | 0.25 or 0.5 mM | 24 h | Elevating the transcription of PRDM16, a master regulator of brown/beige adipogenesis, by inducing the active DNA demethylation of PRDM16 the promoter, which might be driven by the activation of AMPK and production of its downstream tricarboxylic acid cycle intermediate α-Ketoglutarate; increase in the expression levels of UCP1, PRDM16, and PPAR-γ | | [33] | In vitro | RAW264.7 | 0–10 μM | 24 h | Inhibition of the expression of both mRNA and protein levels of proinflammatory cytokines (TNF-α, IL-6, IL-1β, MCP-1) and ER stress genes (CHOP, ATF4, and XBP-1) significantly; inhibition of PA/LPS-induced inflammatory responses through modulating ER stress-mediated ERK1/2 activation in macrophages and hepatocytes | | [34] | In vitro | HepG2 | 1.25, 2.5, and 5 μM | 24 h | Berberine treatment similarly prevented lipid accumulation by regulating the protein expression of ATGL, GK, PPAR-α, CPT-1, ACC1, FAS, and CD36 |
| | In vivo studies | | [12] | In vivo | Rats (N = 16) | 100 and 300 mg/kg/day/HFD | 8 weeks | BBR-treated rats had reduced liver wet weight, improved liver steatosis, and a significant decrease in liver TG levels, while ALT, AST, TC, TG, and LDL serum levels significantly decreased and MTTP levels were significantly upregulated. In conclusion, BBR treatment ameliorated the fatty liver induced by a high-fat diet in rats. Furthermore, BBR reversed the abnormal expression of MTTP and LDLR in rats with high-fat diet induced-NAFLD | | [35] | In vivo | Rats/high-fat diet (N = 8) | 300 mg/kg/day/oral | 8 weeks | Improving liver histopathology and serum proinflammatory cytokines (TNF-α, IL-6) and free fatty acid (FFA) levels; amelioration nonalcoholic steatohepatitis through, at least partly, restoring the Treg/Th17 ratio; regulating the chemerin/CMKLR1 signaling pathway to reduce liver inflammation and reducing lipid deposition | | [36] | In vivo | Rats (N = 16) | 100 mg/kg/day IP | 16 weeks | Reduction in both body and liver weight, TG, TC, ALT, AST, HDL-C, and LDL-C; increase in the protein expression levels of SIRT3, p-AMPK, p-ACC, and CPT-1A in the liver; attenuating liver injury with the HFD | | [17] | In vivo | Mice (N = 10)/normal chow diet | 3 00 mg/kg/day oral | 4 weeks | Reduction in hepatic TG accumulation and the expression of hepatic SCD1 and other TG synthesis-related genes; attenuating hepatic steatosis through the activation of AMPKSREBP 1c-SCD1 pathway | | [37] | In vivo | Rats (N = 10) high-fat diet | 300 mg/kg | 4 weeks | Alleviating HFD-induced suppression of fatty acid β-OX through, at least partly, SIRT3-mediated LCAD deacetylation; decrease in the TG, TC, LDL levels, and body weight; increase in the HDL levels and insulin sensitivity; suppression of the expression of lipogenesis genes including SREBP-1c, SCD1, and FAS FAO; increase in the transcriptional expression of PPARa and CPT-1a | | [8] | In vivo | Rats (N = 20) high-fat diet | 250 mg/kg/d | 8 weeks | Increase in the expression of AMPK; reduction in the TG, TC, AST, and ALT levels; inhibition of the expression of TNF-α, IL-6, CCL19, TLR4, NF-κB-p65, SREBP-1c, and FAS; improving HFD-induced steatosis | | [38] | In vivo | Rats/high-fat diet (N = 11) | 150 mg/kg/oral | 12 weeks | Decrease in firmicutes and cyanobacteria; reduction in gut permeability and improvement of the intestinal barrier in NAFLD rats | | [39] | In vivo | Rats (N = 20) high-fat diet | 150 mg/kg/d | 16 weeks | Reduction in weight loss, lipid profiles, and HOMA-IR; elevating ISI; reduction in rates of glucose appearance, GNG, and hepatic lipogenesis; an increasing trend in the rate of fatty acid β oxidation in skeletal muscle; attenuating the ectopic liver fat accumulation | | [25] | In vitro | Mice (N = 7)/MCD diet | 200 mg/kg/d | 5 weeks | Reduction in the levels of TG, TC, LDL, TG, BUN creatinine, AST, and ALT; inhibition of the accumulation of hepatic lipoperoxides; down-regulation of the expression of the mRNA levels of SREBP-1c, CHREBP, FAS, (TGF) β, α-SMA, CYP2E1, CYP4A10, and C/EBPβ; suppression of the expression of TNF-α and IL-6 in the liver; increase in the CAT; reduction in the mRNA expression of ATF6, XBP1, ATF4, P-PERK, P-EIF2α, and CHOP; alleviating liver steatosis confirmed by biochemical analysis of the hepatic triglyceride content; decrease in the TG, TC, AST, ALT, and TBARS levels | | Berberine had a strong antifibrotic effect, which was displayed by Masson’s trichrome staining and hydroxyproline measurement | | [40] | In vivo | Mice (N = 10)/HFHC | 0.2 g/kg | 12 week | Reduction in body weight, serum total cholesterol, triglyceride levels, liver index, steatosis score, serum ALT, and AST levels; suppression of NE expression in liver tissues; upregulation of α1-AT levels; decrease in liver mRNA levels of CXCR4, CXCL12, the mRNA expression of RAS, PLC-β, PI3K, AKT, NF-κB, IL-1, and IL-8 | | [13] | In vivo | Mice (N = 10)/normal chow diet | 300 mg/kg/day | 8 weeks | Improvement of liver histopathology, serum proinflammatory cytokines, and free fatty acid (FFA) levels; reduction in the mRNA expression of Angptl2, NF-κB, Foxo1 in the liver, the expression of CCL2, TNF-α, and CCR2 in the liver | | [41] | In vivo | Rats (N = 6)/HF diet | 150 mg/kg/oral | 6 weeks | Upregulation of the mRNA expression level of AdipoR2, GLUT4; decrease in the AST, ALT, TC, TG, FFA, LDL, insulin, glucose, MDA, TNF-α, body weight, and liver weight; increase in levels of HDL, SOD, and adiponectin; suppression of the expression of pho-ERK/ERK | | [42] | In vivo | Rats (N = 32) high-fat diet | 25, 50 and 100 mg/kg oxyberberine 100 mg/kg/berberine oral | 8 weeks | Alleviating inflammation via downregulating the mRNA expression of MCP-1, Cd68, Nos2, Cd11c, and enhancing Arg1 mRNA expression in white adipose tissue with oxyberberine and berberine treatment; increase in the expression of AMPK; an inhibition of aberrant phosphorylation of IRS-1; upregulating the downstream protein expression and phosphorylation (PI3K, p-Akt/Akt, and p-GSK-3β/GSK-3β) to improve hepatic insulin signal transduction with the administration of both oxyberberine and berberine treatment | | [43] | In vivo | Rats (N = 10) high-fat diet | 10 mg/100 g body weight | 10 weeks | No effect on the levels of γ-GT, TC, HDL, LDL, and IL-10 in rats; decrease in the levels of, ALT, AST, TG; suppression of IL-17, IFNγ, TNF-α, IL-8, and IL-6; increase in the levels of TGF-β and body weight | | [44] | In vivo | Mice (N = 7) | 10 mg/kg/oral high-fat diet | 7 days | Upregulation of the expression of hepatic CD36 and triglyceride levels in normal diet-fed mice | | [45] | In vivo | Rats (N = 8)/oral high-fat diet | 300 mg/kg/oral high-fat diet | 6 weeks | Reduction in serum ALT, AST, TG, FFA, and glucose; increase in hepatic levels of glycogen; inhibition of the expression of SREAP-1c, FAS, TLR-4, TRL-9, NLRP3, and ASC in the liver; reduction in the expression levels of IL-1β, TNF-α, IL-8, and IL-6 in serum and liver; no effect on the expression levels of PPAR-α | | [46] | In vivo | Rats (N = 12) oral high-fat diet | 200 mg/kg/oral high-fat diet | 12 weeks | Alleviating hepatic steatosis and inflammatory cell infiltration; reduction in the NAFLD activity scores, the NAS scores, serum levels of ALT, AST, TC, LDL-C, the levels of TNF-α, IL-6, and IL-1β, the expression of TLR4, MyD88, and NF-κB in the liver tissues; reversing the nuclear translocation of NF-κB in the primary liver cells | | [47] | In vivo | Mice (N = 11) oral high-fat diet | 200 mg/kg/oral high-fat diet | 5 weeks | Inhibition of the expression of IL-1, TNF-α, IL-6, CD-14, the expression levels of IL-1β, TNF-α, IL-8, and IL-6 in serum and liver; restoring the gut microbiota; decrease in body weight, the levels of TG, TC, LDL, FBG, insulin, HOMA-IR, NAS, steatosis score, AST, and ALT | | [48] | In vivo | Mice (N = 10) | aa/oral HFHC | 12 weeks | Reduction in the levels of TC, LDL, glucose, AST, and ALT; increase in HDL levels; decrease in body weight and liver weight, the expression levels of FASN, SCD1, SREBP1c, IL-6, IL-1β, CD68, F4/80, MCP-1, TNF-α, the expression levels of angiogenic factors such as CD31 and VEGFR; suppression of phosphorylation of p38MAPK and ERK as well as COX2 expression | | [49] | In vivo | Rats (N = 10) | 25 mg/kg/oral HFD | 16 weeks | Restoring the expression of L-PK by the demethylation of L-PK promoter; increase in acetylation levels of histone H3K18, H3K9, H4K8, and H4K12 around L-PK; decrease in body weight, visceral fat, and liver weight | | [50] | In vivo | Rats (N = 10) | 100 mg/kg/oral HFD | 8 weeks | Inhibition of the expression levels of the SREBP-1c, pERK, NF-κB, TNF-α, and pJNK; increase in the expression of caveolin-1, the HDL, and GPX levels; decrease in the TG, TC, LDL, ALT, AST, ALP, FSG, FSI levels, body weight, and visceral fat | | [23] | In vivo | Rats (N = 10) | 100 mg/kg/oral HFD | 12 weeks | Reduction in inflammation in both the liver and adipose tissue as indicated by the reduction of the phosphorylation state of JNK1 and the mRNA levels of proinflammatory cytokines; decrease in hepatic steatosis, as well as the expression of acetyl-CoA carboxylase and fatty acid synthase; no effect on the phosphorylation state of AMPK in both the liver and adipose tissue of HFD-fed mice; improving systemic insulin sensitivity and glucose homeostasis; decrease in liver mRNA levels of IL-1β and TNF-α; no effect on liver mRNA levels of IL-6; amelioration of obesity-associated hepatic steatosis involves in a decrease in liver lipogenesis; decrease in the mRNA levels of genes related to lipogeneses such as ACC, FAS, CPT1a, and SREBP1c | | [51] | In vivo | Rats (N = 10) | 100 mg/kg/oral HFD | 4 weeks | Reduction in liver TG contents, the FIN levels; no effect on the serum ALT, AST TG, TC, LDL, HDL levels, FBG levels, and IR protein levels; increase in GIR; upregulation of IRS-2 mRNA expression in high fat-diet fed rat livers with berberine or pioglitazone treatments for 4 weeks | | [19] | In vivo | Mice (N = 16) | 50 mg/kg and 150 mg/kg/oral HFD | 4 weeks | Inhibition of the expression of mRNA levels of FASN, Fabp1 SLC27A1, α-SMA, TGF-β1, FABP1, CYP2E1, ATF-4, CHOP TLR4, p-NF-κB/NF-κB, and p-I-κB/I-κB; increase in the expression levels of PPAR-α, GSH, and ACOX1 in mice | | Decrease in serum levels of MDA, TNF-α, IL-1β, IL-6, the levels of liver TG, liver TC, LDL, FBG, insulin, HOMA-IR, NAS, ALT, AST steatosis score, and body weight | | [22] | In vivo | Mice (N = 16) | 200 mg/kg/oral MCD | 4 weeks | Alleviating hepatic lipid accumulation, plasma lipid levels, hepatic lipid deposition, ALT, and AST activities; reduction in steatosis by increasing ABCA1 protein levels through PKCd to reduce the phosphorylation of serine residues in ABCA1 | | [18] | In vivo | Mice (N = 5) | 100 mg/kg/oral MCD | 4 weeks | Decrease in lipid accumulation; ameliorating ROS and lipid peroxides, TNF-a expression, and phosphorylation of NF-κB p65 | | [31] | In vivo | Mice (N = 16) | 20 and 40 mg/kg/oral HFD | 4 weeks | Reduction in serum levels of MDA, TG, TC, MDA, ALT; increase in GSH in mice, the expression levels of AMPK, ACO, MCAD, ABCG5, and MTTP; downregulating the expression of the mRNA levels of SREBP1c, SREBP2, TNF-α, and IL-1β by demethylene berberine | | [52] | In vivo | Rats (N = 16) | 100 mg/kg/oral HFD | 4 weeks | Decrease in serum levels of insulin, HbA1c, leptin, adiponectin, TG, phospholipids, albumin, and ALP; increase in HDL in mice; no effect on creatinine, total bilirubin, creatine kinase, acid phosphatase, LDH, AST, ALT, γ-glutamyl transferase, free fatty acids, atherogenic index; downregulating the expression of ROS; improving hepatic mitochondrial function possibly via activation of SirT3 | | [38] | In vivo | Rats (N = 11) | 150 mg/kg/oral HFD | 16 weeks | Reduction in body weight, gut permeability, and the variability of intestinal flora; improvement of the intestinal barrier in NAFLD rats | | [53] | In vivo | Rats (N = 6) | Single-dose/HFD | 48 h | Mitigation in serum levels of ALT, AST, and TG; no effect on the levels of epididymal fat, brown fat, liver weight, body weight, HDL-c, and TC | | [32] | In vivo | Rats (N = 10) | 1.5 mg/kg/day/oral HFD | 8 weeks | Facilitating brown adipocyte differentiation; increase in the transcription of PRDM16, a master regulator of brown/beige adipogenesis, by inducing the active DNA demethylation of PRDM16 promoter, which might be driven by the activation of AMPK and production of its downstream tricarboxylic acid cycle intermediate α-Ketoglutarate; no impact on the BAT thermogenesis in adipose-specific AMPKa1 and AMPKa2 knockout mice | | [54] | In vivo | Rats (N = 10) | 162 and 324 mg/kg/day/oral HFD | 12 weeks | Downregulating the expression levels of mRNA and UCP2; reduction in the levels of TG, TC, and LDL; increase in HDL levels | | [14] | In vivo | Mice (N = 10) | 200 mg/kg/oral HFD | 16 weeks | Reduction in triglyceride accumulation in the liver of HFD-fed mice, Nox2-dependent cytoplasmic ROS production, and mitochondrial ROS production | | [55] | In vivo | Mice (N = 10) | 50 mg/kg/oral HFS | 6 weeks | Downregulating the expression levels of FFAs G6PDH and G3PDH; upregulating the expression levels of PPAR-γ; decrease in serum levels of IR, LDL, TC, and TG; increase in HDL levels | | [28] | In vivo | Mice (N = 10) | 50 mg/kg/oral HFS | 28 days | Decrease in the expression levels of all components of the NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome caspase 1, pannexin-1, and hepatic levels of mature IL-1β, TNF-α, ALT; increase in GSSH levels; decrease in macrophages by preincubation with berberine | | [13] | In vivo | Rats (N = 8) | 300 mg/day high-fat diet comprising 21.6% protein, 36.1% fat, 42.3% carbohydrate; 82.75% basal diet + 10% lard, 2% cholesterol, 0.25% bile salt, and 5% egg yolk powder | 12 weeks | Reduction in proinflammatory cytokines (CCL2, TNF-α); increase in the infiltration of inflammatory cells in the liver; suppression of the expression mRNA and protein levels of Angptl2, NF-κB, and foxo1 on different degrees | | [27] | In vivo | Rats (N = 10) | 50 mg/kg/oral HFD (32.6% carbohydrate, 51.0% fat, and 16.4% protein) | 16 weeks | Reduction in the levels of TC and LDL in the liver | | [56] | In vivo | Rats (n = 6) | 200 mg/kg/oral HFD (32.6% carbohydrate, 51.0% fat, and 16.4% protein) | 48 h | Reduction in the levels of ALT, AST, TG, TC, and LDL and increase in the levels of HDL | | Also, berberine significantly changes the expression level of liMTTP; CPT-1α, GCK; LDLR, L-PK | | [12] | In vivo | Rats (N = 23) | 50 mg/kg/oral HFD (composed of 80% regular chow, 8% yolk powder, 10% lard oil, 1.5% cholesterol, and 0.5% bile salt) | 16 weeks | Decrease in body weight, hepatic wet weight, NAS score, serum levels of TC, TG, MTTP, FBG, ApoB, and LDLR; increase in HDL levels | | [51] | In vivo | Rats (N = 10) | 187.5 mg/kg/day/HFD | 4 weeks | Berberine may improve insulin resistance of NAFLD by upregulating mRNA and protein levels of IRS-2 | | [34] | | Mice (N = 24) | 10, 20, 40 mg/kg | 4 weeks | Berberine treatments could significantly improve hepatic steatosis and insulin resistance in high-fat diet (HFD)-fed mice BBR, could maintain glucose homeostasis via GLUT2, GSK3β, and G6Pase in HFD-fed mice |
| | Human studies | | [32] | Clinical trails | Human (N = 20 patients) | 0.5 g | 1 month | Decrease in BMI, HOMA-IR, and body weight; increase in HDL levels; no effect on the serum levels of insulin and FBG | | [53] | Clinical trials | Human (N = 80 patients) | 0.5 g | 16 weeks | Reduction in serum levels of APO-A, APO-B, TC, TG, BMI, and body weight; no effect on the levels of γ-GT, ALT, ASTAPO-E, LDL, Hb A1C, HOMA-IR, and serum insulin; increase in HDL levels | | [56] | Clinical trials | Human (N = 55 patients) | 0.5 g | 16 weeks | Berberine significant reduction in body weight, AST, APO-E TG. TC, HOMA-IR but did not change in γ-GT, ALT, LDL, HDL, APO-A | | [57] | Clinical trials | Human (N = 67 patients) | 500 and 100 mg | 18 weeks | Berberine significantly decreases HbA1c, fasting insulin, fasting plasma glucose, LDL-C, ALT, AST, GGT, BMI, and liver fat content | | [58] | Clinical trials | Human (N = 50 patients) | 6.25 g | 7 weeks | Berberine had no significant impact on FBS, ALP, fasting SGOT, SGPT, TG, TC, HDL LDL, ALP, BMI |
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