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Journal of Diabetes Research
Volume 2013 (2013), Article ID 956737, 10 pages
http://dx.doi.org/10.1155/2013/956737
Research Article

Effect of (dipic-Cl) on Lipid Metabolism Disorders in the Liver of STZ-Induced Diabetic Rats

College of Life Sciences, University of Chinese Academy of Sciences, No. 19A YuQuan Road, Beijing 100049, China

Received 21 December 2012; Accepted 24 February 2013

Academic Editor: Gordana Kocic

Copyright © 2013 Fang Liu 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.

Abstract

Vanadium complexes are potent antidiabetic agents for therapeutical treatment of diabetes. In the present study, we investigated the hypolipidemic effect of (dipic-Cl)(H2O)2 (V4dipic-Cl) in liver of streptozotocin- (STZ-)-induced diabetic rats. We found that diabetic animals exhibited hepatic inflammatory infiltration and impaired liver function along with triglyceride (TG) accumulation in the liver. V4dipic-Cl treatment not only ameliorated liver pathological state but also reduced hepatic TG level. Moreover, the upregulation of fatty acid translocase (FAT/CD36) mRNA (4.0-fold) and protein (8.2-fold) levels in the liver of diabetic rats were significantly reversed after V4dipic-Cl treatment. However, no significant effects of V4dipic-Cl on the mRNA expression of fatty acid metabolism-related fatty acid bounding protein 1 (FABP1) and fatty acid transporter 5 (FATP5) were observed. These results suggest that the modification of lipid metabolism-related FAT/CD36 in the liver of diabetic rats is likely involved in the hypolipidemic effects of V4dipic-Cl.

1. Introduction

Insulin dependent diabetes mellitus (IDDM), type 1 diabetes, is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing β-cell of the pancreas. The deficiency or complete lack of insulin secretion leads to elevated blood glucose level [1, 2]. Patients with type 1 diabetes present lipid disorders or hyperlipidemia, including elevated levels of total serum cholesterol (TC), triglycerides (TG) [3], low-density lipoprotein (LDL-c), apolipoprotein A (ApoA), apolipoprotein B (ApoB) [4], malondialdehyde (MDA) [4, 5], very low-density lipoprotein (VLDL), and low level of high density lipoprotein (HDL-c) [6]. It is well known that the liver is a central organ in lipogenesis, gluconeogenesis, and cholesterol metabolism [7]. Hepatic lipid metabolism is influenced by the balance between the degradation and synthesis and/or import and export of triglyceride (TG) and fatty acids (FA). Fatty acids are important for many biological functions. Generally, fatty acids are degraded through β-oxidation or esterified and then stored as TG. Hepatic TG accumulation finally resulting in hepatic steatosis [8].Moreover, the FA transport process appears to be disturbed in obesity and diabetes mellitus [9].

Transport of unesterified FA into cells is a complex process involving protein catalysis [10]. Accumulating evidences proved that free fatty acids are taken up by the hepatocytes in a facilitated fashion rather than by passive processes [7, 11]. It is well known that fatty acid translocase is abundantly expressed in tissues with high metabolic capacity for fatty acids. A number of studies have shown that fatty acid translocase (FAT/CD36), fatty acid bounding protein (FABP), and fatty acid transporter (FATP) are membrane glycoproteins present on mononuclear phagocytes, adipocytes, and hepatocytes with multiple functions, which have also been identified to facilitate FA uptake and β-oxidation [1215]. Several studies have demonstrated that FAT/CD36 as a shared transcriptional target is regulated by liver X receptor (LXR), pregnane X receptor (PXR), and aryl hydrocarbon receptor (AhR) [9, 1618]. FA uptake into cells is regulated by altering the expressing of FAT/CD36 [9]. Overexpression of FAT/CD36 results in an increased rate of FA uptake and increased rate of FA metabolism [19]. Fatty acids are taken up into the cells and temporarily stored in a triglyceride pool. FA will be finally oxidized in mitochondria by means of carnitine palmitoyl transferase 1 (Cpt1) and peroxisomal acyl-coenzyme A oxidase 1 (ACOX1).

The insulin-mimetic properties and antidiabetic effects of vanadium compounds have been widely documented both in vivo and in vitro [2022]. Vanadium compounds stimulate glycogen synthesis [23] and lipogenesis [24] and inhibit lipolysis [24, 25]. Recently, various organic vanadium compounds with dipic, dipic-OH, or dipic-NH2 as organic ligand were reported as antidiabetic agents with little side effects and higher absorption than the simple salts [22, 2628]. Moreover, it was observed that vanadate can restore the altered lipogenic enzyme activities to the normal level [29]. Our previous studies showed that vanadium compounds treatment potentially ameliorate lipid metabolism in diabetes [2, 22, 3033]. However, the underlying mechanisms are not completely understood. Therefore, the aim of the study was an attempt to elucidate the hypolipidemic effect of V4dipic-Cl, if any, in regulating hepatic FAT/CD36-induced FA uptake and TG accumulation in STZ-induced diabetic rats. Moreover, serum biochemical parameters and histopathological examination were used to evaluate the side effect of V4dipic-Cl on hepatic functions in diabetic rats.

2. Materials and Methods

2.1. Chemicals

STZ was purchased from Sigma (Sigma-Aldrich, USA) H2dipic-Cl and V4dipic-Cl were gifts from Dr. Debbie C. Crans (Colorado State University, USA) [32]. Tissue triglyceride (TG) kit was purchased from Pplygen (Pplygen, China). RNA isolation reagent, UltraSYBR mixture, and β-actin antibody were purchased from Beijing CoWin Bioscience (China). RNA reverse transcription reagents were from Promega (USA). Radio immunoprecipitation assay lysis buffer (RIPA), HRP-labeled goat anti-rabbit IgG, HRP-labeled goat anti-mouse IgG, and electrochemiluminescence (ECL) reagent were purchased from Beyotime (China). FAT/CD36 antibody was from Santa (Santa Cruz, USA). All other chemicals used were of analytical grade.

2.2. Animals

Male Wistar rats were purchased from Beijing Academy of Military Medical Sciences. The animals were maintained under standard conditions (12 h light/dark cycle, ) and had free access to standard laboratory chow and water. The animals were cared for in accordance with the principles of the Guide for Care and Use of Experimental Animals.

2.3. Treatment Procedure

Diabetes was induced by a single intravenous injection of freshly prepared STZ (40 mg/mL; 55 mg/kg body weight) in 0.1 mol/L citrate buffer (pH 4.5). The control rats were only injected with an equal volume of citrate buffer. Animals with a fasting blood glucose level higher than 13.3 mM were considered to be diabetic rats. Normal and diabetic rats were randomly divided into four groups: Control group (C, ), Diabetic group (D, ), H2dipic-Cl-treated group (L, ), and V4dipic-Cl-treated group (V4, ). V4dipic-Cl was orally administrated to diabetic rats in drinking water at a concentration of 50 μg V/mL daily for 28 days. We have selected this concentration of vanadium on the basis of earlier reports and the same has also been standardized in our laboratory to exhibit the glucose-lowering effects in STZ-induced diabetic animals [2, 30, 31, 3336]. In this present study, fresh solutions of H2dipic-Cl and V4dipic-Cl were prepared every day and were given to the animals through drinking bottles.

2.4. Blood and Tissue Collection and Homogenate Preparation

At the end of the treatment schedules, all animals were sacrificed. Blood was collected from the abdominal vein with a microsyringe. Serum was separated at 3,000 rpm for 15 min. The livers were perfused in situ with saline and then were immediately removed, collected, and stored in liquid nitrogen. Liver tissue homogenates were prepared in lysis buffer using an electric homogenizer.

2.5. Biochemical Analysis

Biochemical parameters in serum, including TC, TG, HDL-c, LDL-c, alanine transaminase (ALT), and aspartate aminotransferase (AST) were determined using an OLYMPUS AU400 chemistry analyzer. Hepatic TG levels were measured by using tissue homogenates. The concentration of TG was determined using a tissue triglyceride assay kit.

2.6. Histological Examination

Sections measuring approximately were taken from the liver of each rat. They were dehydrated through graded solutions of alcohol ending in two changes of absolute alcohol for 2 h each. They were cleared in 2 changes of xylene, infiltrated in 2 changes of paraffin wax for 2 h each, and embedded in molten paraffin wax. Sections were cut at 4 μm with rotary microtome and stained with hematoxylin and eosin (H&E). Futher, the stained slides was observed under light microscope at 10x and 40x magnifications for histopathological examination.

2.7. Quantitative Analysis of Gene Expression

Real-time PCR was carried out using the method described by Xue et al. [37]. Briefly, total RNA was extracted from the frozen liver by RNA Isolation Reagent. Then 1 μg of total RNA was subjected to the reserve transcription reaction. The cDNA was used as a template to examine the mRNA levels of FAT/CD36, FATP5, FABP1, Cpt1α, ACOX1, ApoB, LXR, PXR, and AhR by using UltraSYBR mixture. β-actin was used as an internal control for normalization. The PCR cycle was as follows: initial denaturation at 95°C for 10 min, followed by 40 cycles of denaturation at 95°C for 30 s, annealing at 60°C for 30 s, and extension at 72°C for 30 s. The primers for target genes are shown in Table 1.

tab1
Table 1: Primers for real-time PCR analysis.

2.8. Western Blot

Liver tissues were lysed in 1 ml of radio immunoprecipitation assay lysis buffer (RIPA) and then centrifuged at 14000 rpm for 5 min. Supernatants were collected and protein content was determined with protein assay kit. The lysates were subjected to sodium dodecyl sulfate polyacrylaminde gel electrophoresis (SDS-PAGE). The gels were transferred to polyvinylidene fluoride (PVDF) membrane by semidry electrophoretic transfer at an electric current 1 mA/cm2 for 90 min. The PVDF membrane was blocked with 5% no-fat milk for 1 h at the room temperature and then incubated with the primary antibody (1 : 1000) overnight at 4°C in a table concentrator. The membrane was washed per 5 min for 4 times prior to incubation in the secondary antibody (1 : 1000) solution for 1 h at the room temperature. Immunoreactive bands were detected with electrochemiluminescence (ECL) reagents according to the manufacturer’s instructions. β-actin was included as a loading control.

2.9. Statistical Analysis

Data are expressed as . The statistical analysis was performed by one-way ANOVA followed by Tukey’s test. Statistical significance was set at .

3. Results

3.1. Serum Parameters

As shown in Figures 1(a)1(c), serum TG, TC, and HDL-c levels in diabetic group were higher than those in control group. However, the level of serum TG was significantly decreased after treatment with V4dipic-Cl. The concentration of TC in diabetic rats remained unchanged after treatment with V4dipic-Cl. The LDL-c levels were not significantly different among the four groups of rats. Moreover, the activities of serum ALT and AST were markedly increased in diabetic rats. However, the ALT and AST activities were decreased in V4dipic-Cl-treated diabetic rats (Figures 1(e) and 1(f)).

fig1
Figure 1: Effects of V4dipic-Cl on serum biochemical parameters in STZ-induced diabetic rats. (a) TG, (b) TC, (c) HDL-c, (d) LDL-c, (e) ALT, (f) AST. C: control group, D: diabetic group, L: H2dipic-Cl-treated group, V4: V4dipic-Cl-treated group. Values are expressed as , . , versus C. , versus D.
3.2. TG Level and Histological Alteration in Liver

The hepatic TG level in diabetic group was higher than that in normal rats, which was significantly decresed after treatment with V4dipic-Cl (Figure 2). In comparison with the control group (Figure 3(a)), the histological alterations were detected in the liver tissue of diabetic rats. Inflammatory cells infiltrate of liver lobules and dilated congested central vein were observed in Figure 3(b). However, the pathological alterations were ameliorated after treatment with V4dipic-Cl (Figure 3(d)) compared to those of H2dipic-Cl-treated diabetic rats (Figure 3(c)).

956737.fig.002
Figure 2: Effects of V4dipic-Cl on hepatic TG level in STZ-induced diabetic rats. C: control group, D: diabetic group, L: H2dipic-Cl-treated group, V4: V4dipic-Cl-treated group. Values are expressed as , . versus C. versus D.
fig3
Figure 3: Effects of V4dipic-Cl on liver histological alterations in STZ-induced diabetic rats: (a) Control group, (b) Diabetic group, (c) H2dipic-Cl-treated group, (d) V4dipic-Cl-treated group (H&E, scale bar = 50 μm, 400x).
3.3. Fatty Acids Transportation in Liver

The mRNA expression levels of FAT/CD36, FABP1, and FATP5 in diabetes group were higher than those in control group (Figure 4). However, the mRNA expression level of FAT/CD36 was significantly decreased after treatment with V4dipic-Cl. Moreover, the mRNA expression levels of FAT/CD36, FABP1, and FATP5 were significantly decreased in the H2dipic-Cl-treated group. In contrast, treatment with V4dipic-Cl did not affect the mRNA expression levels of FABP and FATP in STZ-induced diabetes.

fig4
Figure 4: Effects of V4dipic-Cl on mRNA expression levels of FAT/CD36, FABP1, and FATP5 and protein level of FAT/CD36 in STZ-induced diabetic rats. C: Control group, D: Diabetic group, L: H2dipic-Cl-treated group, V4: V4dipic-Cl-treated group. Values are expressed as mean ± SEM, . , versus C. , versus D.
3.4. Transcription Factors of FAT/CD36 in Liver

The mRNA expression levels of LXR and PXR in diabetic group were significantly higher than those in control group. Moreover, the mRNA expression levels of LXR, PXR, and AhR were significantly elevated after treatment with V4dipic-Cl (Figure 5). However, the mRNA expression levels of LXR, PXR, and AhR were significantly decreased in the H2dipic-Cl-treated group as compared with the diabetic group (Figures 5(a)5(c)).

fig5
Figure 5: Effects of V4dipic-Cl on mRNA expression levels of LXR, PXR, and AhR. C: Control group, D: Diabetic group, L: H2dipic-Cl-treated group, V4: V4dipic-Cl-treated group. Values are expressed as mean ± SEM, . versus C. versus D, versus D.
3.5. Fatty Acids Oxidation in Liver

Carnitine palmitoyltransferase Iα(Cpt1α) is located on the outer membrane of mitochondria and participates in fatty acid transportation into mitochondria. As shown in Figure 6(a), the mRNA expression level of Cpt1α was increased in diabetic group. However, the mRNA expression level of Cpt1α was significantly decreased after treatment with V4dipic-Cl and H2dipic-Cl. In contrast, the mRNA expression levels of peroxisomal acyl-coenzyme A oxidase 1 (ACOX1) and apolipoprotein B (ApoB) were not significantly different among the four groups of rats (Figures 6(b) and 6(c)).

fig6
Figure 6: Effects of V4dipic-Cl on mRNA expression levels of Cpt1α, ACOX1 and ApoB in STZ-induced diabetic rats. C: Control group, D: Diabetic group, L: H2dipic-Cl-treated group, V4: V4dipic-Cl-treated group. Values are expressed as mean ± SEM, . versus C. versus D.

4. Discussion

Accumulating evidences have demonstrated that STZ-induced diabetes mellitus and insulin deficiency lead to hyperglycemia [38] and dyslipidemia [39]. It has been previously reported that hyperglycemia and dyslipidemia are associated with specific diabetic complications and disturbances in various tissues, such as diabetic nephropathy and cardiovascular diseases, but only limited data is available on the possible association between diabetic complications and liver function [30, 40]. The present study was designed to evaluate the effects of V4dipic-Cl on lipid metabolism disorders in the liver of STZ-induced diabetic rats.

It has been recognized that dyslipidemia is a frequent complication in all types of diabetes which can range from hypercholesterolemia to hyperlipoproteinemia [39]. Hyperlipidemia could be a factor for fatty liver formation [41]. In the present study, as expected serum TG and TC as well as hepatic TG levels were elevated in the diabetic group compared to those in the control group, which is consistent with other studies [35]. However, the elevated level of serum TG in diabetic rats was significantly decreased after treatment with V4dipic-Cl. This is in agreement with the evidence that vanadium compounds decrease the high levels of TG in serum and liver [29, 30]. Moreover, the altered expression of genes involved in lipid biosynthetic pathways in diabetes returned to normal level after treatment with vanadium compounds [2, 42].

Hyperglycemia is associated with liver dysfunction in IDDM [30, 41]. Elevated activities of serum aminotransferases are a common sign of liver diseases [30, 40]. Typical serum biochemical parameters, such as ALT and AST, are often examined to evaluate whether the liver is damaged or diseased. In the present study, our findings of elevated serum ALT and AST levels are in agreement with the findings of Zafar et al. [41]. The increase in ALT and AST activities may be due to the cellular damage in the liver caused by STZ-induced diabetes. After 28 days of treatment with V4dipic-Cl, the activities of both ALT and AST were significantly decreased. The result suggests that V4dipic-Cl may be capable of ameliorating the impaired liver function in STZ-induced diabetic rats, which is consistent with previously reported results for treatment with vanadium complexes [30].

Ohno et al. [43] described the fatty liver and hyperlipidemia in IDMM of treated shrews. In the present study, the histopathology of liver showed a development of the lesions which seems to be due to STZ treatment. Most liver sections showed inflammatory cells infiltrate of liver lobules and dilated congested central vein. These findings are in agreement with the findings of Degirmenci et al. and Zafar et al. who showed dilatation of veins and liver fibrosis in their study [41, 44]. However, we found that treatment with V4dipic-Cl dramatically improved pathologic lesions seen in the liver.

Free fatty acids are a major component of blood lipids and plays a key role in regulating blood lipid levels, especially in triglyceride metabolism [45]. In addition, elevated plasma FA is a risk factor for metabolic syndrome, which can lead to hyperlipidemia, fatty liver, and insulin resistance [46, 47]. FAT/CD36 is a rate-limiting enzyme in high-affinity peripheral FA uptake in the liver [48]. Thus, FAT/CD36 is an important regulator in the uptake of fatty acids in the liver and the pathogenesis of fatty liver disease.

It was reported that FA uptake is reduced in FAT/CD36 null mice [49] and is reconstituted when FAT/CD36 is reexpressed [50]. Luiken et al. reported that FAT/CD36 mRNA expression is increased in streptozotocin-induced diabetes [51]. Thus, FAT/CD36 may participate in the pathogenesis of liver ectopic fat deposition [16]. In the present study, we found that the mRNA expression level of FAT/CD36 in diabetes group was significantly higher than that in control group. However, V4dipic-Cl treatment significantly resulted in decrease in the mRNA and protein expression levels of FAT/CD36 in V4dipic-Cl-treated group treatment. In addition to FAT/CD36, Goldberg and Ginsberg described that fatty acid-binding protein (FABP) and fatty acid transport protein (FATP) can mediate fatty acid uptake in the liver [52]. In the present study, the mRNA expression levels of FABP1 and FAFP5 were increased in diabetic group, which is consistent with the previous report that the expression of FABP is increased in STZ-induced diabetes [53]. However, treatment with V4dipic-Cl did not affect the expression of FABP and FATP in STZ-induced diabetes. Thus, we propose that V4dipic-Cl can mainly regulate fatty acid transporter FAT/CD36 in liver [54].

Zhou et al. described that nuclear acceptors AhR, PXR, and LXR cooperate to promote hepatic steatosis by increasing the expression of FAT/CD36 [16, 17]. More recently, Cheng et al. demonstrated that the mRNA expression level of LXR was markedly increased in diabetic rats [55]. Harano et al. reported that fenofibrate, PPARα agonist, dramatically reduced hepatic triglyceride levels by activating expression of ACOX1 and Cpt1α involved in fatty acid turnover [56]. In the present study, we also found that the mRNA expression levels of LXR, PXR, and Cpt1α were increased in diabetic group. However, treatment with V4dipic-Cl did not decrease the mRNA expression levels of LXR, PXR, and AhR as well as the FA oxidation-related Cpt1α and ACOX1 as compared to H2dipic-Cl-treated diabetic rats. It is possible that some other mechanisms may contribute to regulation of FAT/CD36 expression through modulating nuclear receptors by vanadium compounds. Our further research will focus on this.

5. Conclusions

This study showed that V4dipic-Cl ameliorates STZ-induced hepatic inflammatory infiltration, liver disfunction, and hepatic TG accumulation. This effects were likely associated with the modification of lipid metabolism-related FAT/CD36 in liver. These results together with the previous observations suggest that V4dipic-Cl can be used as a therapeutic agent for treatment of metabolic disorder in diabetes mellitus.

Acknowledgment

This work was financially supported by China National Natural Sciences Foundation (no. 20871120, 11075207).

References

  1. D. Daneman, “Type 1 diabetes,” The Lancet, vol. 367, no. 9513, pp. 847–858, 2006. View at Publisher · View at Google Scholar · View at Scopus
  2. D. Wei, M. Li, and W. Ding, “Effect of vanadate on gene expression of the insulin signaling pathway in skeletal muscle of streptozotocin-induced diabetic rats,” Journal of Biological Inorganic Chemistry, vol. 12, no. 8, pp. 1265–1273, 2007. View at Publisher · View at Google Scholar · View at Scopus
  3. R. P. F. Dullaart, “Plasma lipoprotein abnormalities in type 1 (insulin-dependent) diabetes mellitus,” Netherlands Journal of Medicine, vol. 46, no. 1, pp. 44–54, 1995. View at Publisher · View at Google Scholar · View at Scopus
  4. F. Erciyas, F. Taneli, B. Arslan, and Y. Uslu, “Glycemic control, oxidative stress, and lipid profile in children with type 1 diabetes mellitus,” Archives of Medical Research, vol. 35, no. 2, pp. 134–140, 2004. View at Publisher · View at Google Scholar · View at Scopus
  5. G. Gallou, A. Ruelland, B. Legras, D. Maugendre, H. Allannic, and L. Cloarec, “Plasma malondialdehyde in type 1 and type 2 diabetic patients,” Clinica Chimica Acta, vol. 214, no. 2, pp. 227–234, 1993. View at Publisher · View at Google Scholar · View at Scopus
  6. B. Vergès, “Lipid disorders in type 1 diabetes,” Diabetes and Metabolism, vol. 35, no. 5, pp. 353–360, 2009. View at Publisher · View at Google Scholar
  7. L. P. Bechmann, R. A. Hannivoort, G. Gerken, G. S. Hotamisligil, M. Trauner, and A. Canbay, “The interaction of hepatic lipid and glucose metabolism in liver diseases,” Journal of Hepatology, vol. 56, no. 4, pp. 952–964, 2012. View at Publisher · View at Google Scholar
  8. S. Nishikawa, K. Doi, H. Nakayama, and K. Uetsuka, “The effect of fasting on hepatic lipid accumulation and transcriptional regulation of lipid metabolism differs between C57BL/6J and BALB/cA mice fed a high-fat diet,” Toxicologic Pathology, vol. 36, no. 6, pp. 850–857, 2008. View at Publisher · View at Google Scholar · View at Scopus
  9. A. Bonen, S. E. Campbell, C. R. Benton et al., “Regulation of fatty acid transport by fatty acid translocase/CD36,” Proceedings of the Nutrition Society, vol. 63, no. 2, pp. 245–249, 2004. View at Publisher · View at Google Scholar · View at Scopus
  10. J. A. Hamilton, “Fatty acid transport: difficult or easy?” Journal of Lipid Research, vol. 39, no. 3, pp. 467–481, 1998. View at Scopus
  11. P. D. Berk, “Regulatable fatty acid transport mechanisms are central to the pathophysiology of obesity, fatty liver, and metabolic syndrome,” Hepatology, vol. 48, no. 5, pp. 1362–1376, 2008. View at Publisher · View at Google Scholar · View at Scopus
  12. N. Abumrad, C. Coburn, and A. Ibrahimi, “Membrane proteins implicated in long-chain fatty acid uptake by mammalian cells: CD36, FATP and FABPm,” Biochimica et Biophysica Acta, vol. 1441, no. 1, pp. 4–13, 1999. View at Publisher · View at Google Scholar · View at Scopus
  13. M. Andersen, B. Lenhard, C. Whatling, P. Erikssson, and J. Odeberg, “Alternative promoter usage of the membrane glycoprotein CD36,” BMC Molecular Biology, vol. 7, no. 1, article 8, 2006. View at Publisher · View at Google Scholar · View at Scopus
  14. X. Su and N. A. Abumrad, “Cellular fatty acid uptake: a pathway under construction,” Trends in Endocrinology and Metabolism, vol. 20, no. 2, pp. 72–77, 2009. View at Publisher · View at Google Scholar · View at Scopus
  15. E. E. Blaak, “Fatty acid metabolism in obesity and type 2 diabetes mellitus,” Proceedings of the Nutrition Society, vol. 62, no. 3, pp. 753–760, 2003. View at Publisher · View at Google Scholar · View at Scopus
  16. J. He, J. H. Lee, M. Febbraio, and W. Xie, “The emerging roles of fatty acid translocase/CD36 and the aryl hydrocarbon receptor in fatty liver disease,” Experimental Biology and Medicine, vol. 236, no. 10, pp. 1116–1121, 2011. View at Publisher · View at Google Scholar
  17. J. Zhou, M. Febbraio, T. Wada et al., “Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARγ in promoting steatosis,” Gastroenterology, vol. 134, no. 2, pp. 556.e1–567.e1, 2008. View at Publisher · View at Google Scholar · View at Scopus
  18. J. M. Pascussi, S. Gerbal-Chaloin, C. Duret, M. Daujat-Chavanieu, M. J. Vilarem, and P. Maurel, “The tangle of nuclear receptors that controls xenobiotic metabolism and transport: crosstalk and consequences,” Annual Review of Pharmacology and Toxicology, vol. 48, pp. 1–32, 2008. View at Publisher · View at Google Scholar · View at Scopus
  19. A. Ibrahimi, A. Bonen, W. D. Blinn et al., “Muscle-specific overexpression of FAT/CD36 enhances fatty acid oxidation by contracting muscle, reduces plasma triglycerides and fatty acids, and increases plasma glucose and insulin,” The Journal of Biological Chemistry, vol. 274, no. 38, pp. 26761–26766, 1999. View at Publisher · View at Google Scholar · View at Scopus
  20. G. Wang, M. He, P. Yi et al., “Comparison of effects of vanadium absorbed by coprinus comatus with those of inorganic vanadium on bone in streptozotocin-diabetic rats,” Biological Trace Element Research, vol. 149, no. 3, pp. 391–398, 2012. View at Publisher · View at Google Scholar
  21. Y. B. Wei and X. D. Yang, “Synthesis, characterization and anti-diabetic therapeutic potential of a new benzyl acid-derivatized kojic acid vanadyl complex,” BioMetals, vol. 25, no. 6, pp. 1261–1268, 2012. View at Publisher · View at Google Scholar
  22. M. Li, D. Wei, W. Ding, B. Baruah, and D. C. Crans, “Anti-diabetic effects of cesium aqua (N,N′-ethylene(salicylideneiminato)-5-sulfonato) oxovanadium (IV) dihydrate in streptozotocin-induced diabetic rats,” Biological Trace Element Research, vol. 121, no. 3, pp. 226–232, 2008. View at Publisher · View at Google Scholar · View at Scopus
  23. T. A. Clark, A. L. Edel, C. E. Heyliger, and G. N. Pierce, “Effective control of glycemic status and toxicity in Zucker diabetic fatty rats with an orally administered vanadate compound,” Canadian Journal of Physiology and Pharmacology, vol. 82, no. 10, pp. 888–894, 2004. View at Publisher · View at Google Scholar · View at Scopus
  24. A. Shisheva and Y. Shechter, “Quercetin selectively inhibits insulin receptor function in vitro and the bioresponses of insulin and insulinomimetic agents in rat adipocytes,” Biochemistry, vol. 31, no. 34, pp. 8059–8063, 1992. View at Scopus
  25. H. Degani, M. Gochin, S. J. D. Karlish, and Y. Shechter, “Electron paramagnetic resonance studies and insulin-like effects of vanadium in rat adipocytes,” Biochemistry, vol. 20, no. 20, pp. 5795–5799, 1981. View at Scopus
  26. D. C. Crans, L. Yang, T. Jakusch, and T. Kiss, “Aqueous chemistry of ammonium (dipicolinato)oxovanadate(V): the first organic vanadium(V) insulin-mimetic compound,” Inorganic Chemistry, vol. 39, no. 20, pp. 4409–4416, 2000. View at Publisher · View at Google Scholar · View at Scopus
  27. D. C. Crans, M. Mahroof-Tahir, M. D. Johnson et al., “Vanadium(IV) and vanadium(V) complexes of dipicolinic acid and derivatives. Synthesis, X-ray structure, solution state properties: and effects in rats with STZ-induced diabetes,” Inorganica Chimica Acta, vol. 356, pp. 365–378, 2003. View at Publisher · View at Google Scholar · View at Scopus
  28. D. C. Crans, J. J. Smee, E. Gaidamauskas, and L. Yang, “The chemistry and biochemistry of vanadium and the biological activities exerted by vanadium compounds,” Chemical Reviews, vol. 104, no. 2, pp. 849–902, 2004. View at Publisher · View at Google Scholar · View at Scopus
  29. D. Gupta, J. Raju, J. Prakash, and N. Z. Baquer, “Change in the lipid profile, lipogenic and related enzymes in the livers of experimental diabetic rats: effect of insulin and vanadate,” Diabetes Research and Clinical Practice, vol. 46, no. 1, pp. 1–7, 1999. View at Publisher · View at Google Scholar · View at Scopus
  30. M. Li, W. Ding, J. J. Smee, B. Baruah, G. R. Willsky, and D. C. Crans, “Anti-diabetic effects of vanadium(III, IV, V)-chlorodipicolinate complexes in streptozotocin-induced diabetic rats,” BioMetals, vol. 22, no. 6, pp. 895–905, 2009. View at Publisher · View at Google Scholar · View at Scopus
  31. M. Li, J. J. Smee, W. Ding, and D. C. Crans, “Anti-diabetic effects of sodium 4-amino-2,6-dipicolinatodioxovanadium(V) dihydrate in streptozotocin-induced diabetic rats,” Journal of Inorganic Biochemistry, vol. 103, no. 4, pp. 585–589, 2009. View at Publisher · View at Google Scholar · View at Scopus
  32. J. J. Smee, J. A. Epps, K. Ooms et al., “Chloro-substituted dipicolinate vanadium complexes: synthesis, solution, solid-state, and insulin-enhancing properties,” Journal of Inorganic Biochemistry, vol. 103, no. 4, pp. 575–584, 2009. View at Publisher · View at Google Scholar
  33. W. Ding, T. Hasegawa, H. Hosaka, D. Peng, K. Takahashi, and Y. Seko, “Effect of long-term treatment with vanadate in drinking water on KK mice with genetic non-insulin-dependent diabetes mellitus,” Biological Trace Element Research, vol. 80, no. 2, pp. 159–174, 2001. View at Publisher · View at Google Scholar · View at Scopus
  34. A. B. Goldfine, D. C. Simonson, F. Folli, M. E. Patti, and C. R. Kahn, “In vivo and in vitro studies of vanadate in human and rodent diabetes mellitus,” Molecular and Cellular Biochemistry, vol. 153, no. 1-2, pp. 217–231, 1995. View at Publisher · View at Google Scholar · View at Scopus
  35. M. O. Leda, D. Carlos, M. C. Alcira, and N. G. Esther, “ALAS1 gene expression is down-regulated by Akt-mediated phosphorylation and nuclear exclusion of FOXO1 by vanadate in diabetic mice,” Biochemical Journal, vol. 442, no. 2, pp. 303–310, 2012. View at Publisher · View at Google Scholar
  36. J. Meyerovitch, P. Rothenberg, Y. Shechter, S. Bonner-Weir, and C. R. Kahn, “Vanadate normalizes hyperglycemia in two mouse models of non-insulin-dependent diabetes mellitus,” Journal of Clinical Investigation, vol. 87, no. 4, pp. 1286–1294, 1991. View at Scopus
  37. J. Xue, W. Ding, and Y. Liu, “Anti-diabetic effects of emodin involved in the activation of PPARγ on high-fat diet-fed and low dose of streptozotocin-induced diabetic mice,” Fitoterapia, vol. 81, no. 3, pp. 173–177, 2010. View at Publisher · View at Google Scholar · View at Scopus
  38. M. K. Saeed, Y. Deng, and R. Dai, “Attenuation of biochemical parameters in streptozotocin-induced diabetic rats by oral administration of extracts and fractions of Cephalotaxus sinensis,” Journal of Clinical Biochemistry and Nutrition, vol. 42, no. 1, pp. 21–28, 2008. View at Publisher · View at Google Scholar · View at Scopus
  39. H. Gylling, J. A. Tuominen, V. A. Koivisto, and T. A. Miettinen, “Cholesterol metabolism in type 1 diabetes,” Diabetes, vol. 53, no. 9, pp. 2217–2222, 2004. View at Publisher · View at Google Scholar · View at Scopus
  40. P. E. T. Arkkila, P. J. Koskinen, I. M. Kantola, T. Rönnemaa, E. Seppänen, and J. S. Viikari, “Diabetic complications are associated with liver enzyme activities in people with type 1 diabetes,” Diabetes Research and Clinical Practice, vol. 52, no. 2, pp. 113–118, 2001. View at Publisher · View at Google Scholar · View at Scopus
  41. M. Zafar, S. Naeem-ul-Hassan Naqvi, M. Ahmed, and Z. A. Kaim Khani, “Altered liver morphology and enzymes in streptozotocin-induced diabetic rats,” International Journal of Morphology, vol. 27, no. 3, pp. 719–725, 2009.
  42. G. R. Willsky, L. H. Chi, Y. Liang, D. P. Gaile, Z. Hu, and D. C. Crans, “Diabetes-altered gene expression in rat skeletal muscle corrected by oral administration of vanadyl sulfate,” Physiological Genomics, vol. 26, no. 3, pp. 192–201, 2006. View at Publisher · View at Google Scholar · View at Scopus
  43. T. Ohno, F. Horio, S. Tanaka, M. Terada, T. Namikawa, and J. Kitoh, “Fatty liver and hyperlipidemia in IDDM (insulin-dependent diabetes mellitus) of streptozotocin-treated shrews,” Life Sciences, vol. 66, no. 2, pp. 125–131, 1999. View at Scopus
  44. I. Degirmenci, S. Kalender, M. C. Ustuner et al., “The effects of acarbose and Rumex patientia on liver ultrastructure in streptozotocin-induced diabetic (type II) rats,” Drugs under Experimental and Clinical Research, vol. 28, no. 6, pp. 229–234, 2002. View at Scopus
  45. U. Julius, “Influence of plasma free fatty acids on lipoprotein synthesis and diabetic dyslipidemia,” Experimental and Clinical Endocrinology and Diabetes, vol. 111, no. 5, pp. 246–250, 2003. View at Publisher · View at Google Scholar · View at Scopus
  46. G. Boden, “Free fatty acids, insulin resistance, and type 2 diabetes mellitus,” Proceedings of the Association of American Physicians, vol. 111, no. 3, pp. 241–248, 1999. View at Publisher · View at Google Scholar · View at Scopus
  47. P. Kovacs and M. Stumvoll, “Fatty acids and insulin resistance in muscle and liver,” Best Practice and Research: Clinical Endocrinology and Metabolism, vol. 19, no. 4, pp. 625–635, 2005. View at Publisher · View at Google Scholar · View at Scopus
  48. G. P. Holloway, V. Bezaire, G. J. F. Heigenhauser et al., “Mitochondrial long chain fatty acid oxidation, fatty acid translocase/CD36 content and carnitine palmitoyltransferase I activity in human skeletal muscle during aerobic exercise,” Journal of Physiology, vol. 571, no. 1, pp. 201–210, 2006. View at Publisher · View at Google Scholar · View at Scopus
  49. M. Febbraio, N. A. Abumrad, D. P. Hajjar et al., “A null mutation in murine CD36 reveals an important role in fatty acid and lipoprotein metabolism,” The Journal of Biological Chemistry, vol. 274, no. 27, pp. 19055–19062, 1999. View at Publisher · View at Google Scholar · View at Scopus
  50. O. Sato, N. Takanashi, and K. Motojima, “Third promoter and differential regulation of mouse and human fatty acid translocase/CD36 genes,” Molecular and Cellular Biochemistry, vol. 299, no. 1-2, pp. 37–43, 2007. View at Publisher · View at Google Scholar · View at Scopus
  51. J. J. F. P. Luiken, Y. Arumugam, R. C. Bell et al., “Changes in fatty acid transport and transporters are related to the severity of insulin deficiency,” The American Journal of Physiology, vol. 283, no. 3, pp. E612–E621, 2002. View at Scopus
  52. I. J. Goldberg and H. N. Ginsberg, “Ins and outs modulating hepatic triglyceride and development of nonalcoholic fatty liver disease,” Gastroenterology, vol. 130, no. 4, pp. 1343–1346, 2006. View at Publisher · View at Google Scholar · View at Scopus
  53. A. Kamijo-Ikemori, T. Sugaya, A. Sekizuka, K. Hirata, and K. Kimura, “Amelioration of diabetic tubulointerstitial damage in liver-type fatty acid-binding protein transgenic mice,” Nephrology Dialysis Transplantation, vol. 24, no. 3, pp. 788–800, 2009. View at Publisher · View at Google Scholar · View at Scopus
  54. A. Chabowski, J. Górski, J. J. F. P. Luiken, J. F. C. Glatz, and A. Bonen, “Evidence for concerted action of FAT/CD36 and FABPpm to increase fatty acid transport across the plasma membrane,” Prostaglandins Leukotrienes and Essential Fatty Acids, vol. 77, no. 5-6, pp. 345–353, 2007. View at Publisher · View at Google Scholar · View at Scopus
  55. Y. Cheng, G. Liu, Q. Pan, S. Guo, and X. Yang, “Elevated expression of liver X receptor alpha (LXRα) in myocardium of streptozotocin-induced diabetic rats,” Inflammation, vol. 34, no. 6, pp. 698–706, 2011. View at Publisher · View at Google Scholar
  56. Y. Harano, K. Yasui, T. Toyama et al., “Fenofibrate, a peroxisome proliferator-activated receptor α agonist, reduces hepatic steatosis and lipid peroxidation in fatty liver Shionogi mice with hereditary fatty liver,” Liver International, vol. 26, no. 5, pp. 613–620, 2006. View at Publisher · View at Google Scholar · View at Scopus