Nonalcoholic fatty liver disease (NAFLD), a premorbid condition, lacks proper management owing to multitude of abnormalities. In this study, we compared the effects of a potent antioxidant, grape seed proanthocyanidins (GSP), and an insulin sensitizer, metformin (MET), in high-fat-fructose-diet- (HFFD-) induced albino Wistar rat model of NAFLD. Either GSP (100？mg/Kg b.w) or MET (50？mg/Kg b.w) or both were administered as therapeutic options. HFFD-fed rats showed abnormal plasma lipid profile, inflammation, and steatosis of the liver when examined by biochemical and histology techniques. Increased lipid storage, lipogenesis, and reduced lipolysis were evident from mRNA expression studies of hepatic lipid droplets (LD) proteins, sterol regulatory element binding 1c (SREBP 1c), and peroxisome proliferator activated receptor-α (PPAR-α). GSP administration to HFFD-fed rats caused 69% reduction in hepatic TG levels, whereas MET caused only 23%. The combination treatment reduced TG levels by 63%. GSP reduced the mRNA expression of SREBP1c and LD proteins and increased that of PPAR-α more effectively compared to MET in HFFD-induced hyperlipidemic rats. Combination of MET and GSP improved the metabolism of lipids effectively, but the effect was not additive in restoring lipid levels. 1. Introduction Nonalcoholic fatty liver disease (NAFLD) has become a global health problem in both adults and children, the prevalence of which has doubled during last 20 years in tune with the increasing incidence of obesity and insulin resistance [1]. Improper regulation of lipogenesis and lipid oxidation is a prime factor in the genesis of fatty liver. Lipogenesis encompasses the processes of fatty acid synthesis and subsequent formation of triglyceride (TG). Sterol regulatory elemental binding protein-1c (SREBP-1c) belongs to a family of transcription factors that are sensitive to cellular availability of cholesterol [2] and promotes fatty acid synthesis and lipid deposition. SREBP-1c regulates lipogenesis by increasing the expression of genes involved in fatty acid biosynthesis such as acetyl CoA carboxylase, fatty acid synthase, and stearoyl CoA desaturase. SREBP-1c has been implicated in the development of human metabolic disorders like obesity, type 2 diabetes, dyslipidemia, atherosclerosis, lipodystrophy, and metabolic syndrome. Lipid reserves are stored in the form of lipid droplets (LDs) intracellularly. LDs, long considered as inert substances, are now recognized for their dynamic role in lipid metabolism. They are structurally similar to circulating lipoproteins,
References
[1]
Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. World Gasteroenterology Organisation Global Guidelines, 2012.
[2]
A. Radhakrishnan, J. L. Goldstein, J. G. McDonald, and M. S. Brown, “Switch-like control of SREBP-2 transport triggered by small changes in ER cholesterol: a delicate balance,” Cell Metabolism, vol. 8, no. 6, pp. 512–521, 2008.
[3]
R. Bartz, W.-H. Li, B. Venables et al., “Lipidomics reveals that adiposomes store ether lipids and mediate phospholipid traffic,” Journal of Lipid Research, vol. 48, no. 4, pp. 837–847, 2007.
[4]
R. Bartz, J. K. Zehmer, M. Zhu et al., “Dynamic activity of lipid droplets: protein phosphorylation and GTP-mediated protein translocation,” Journal of Proteome Research, vol. 6, no. 8, pp. 3256–3265, 2007.
[5]
D. L. Brasaemle, “The perilipin family of structural lipid droplet proteins: stabilization of lipid droplets and control of lipolysis,” Journal of Lipid Research, vol. 48, no. 12, pp. 2547–2559, 2007.
[6]
K. Matsusue, “A physiological role for fat specific protein 27/cell death-inducing DFF45-like effector C in adipose and liver,” Biological and Pharmaceutical Bulletin, vol. 33, no. 3, pp. 346–350, 2010.
[7]
N. A. Ducharme and P. E. Bickel, “Minireview: lipid droplets in lipogenesis and lipolysis,” Endocrinology, vol. 149, no. 3, pp. 942–949, 2008.
[8]
C. Thiele and J. Spandl, “Cell biology of lipid droplets,” Current Opinion in Cell Biology, vol. 20, no. 4, pp. 378–385, 2008.
[9]
J. K. Zehmer, Y. Huang, G. Peng, J. Pu, R. G. W. Anderson, and P. Liu, “A role for lipid droplets in inter-membrane lipid traffic,” Proteomics, vol. 9, no. 4, pp. 914–921, 2009.
[10]
R. Zechner, P. C. Kienesberger, G. Haemmerle, R. Zimmermann, and A. Lass, “Adipose triglyceride lipase and the lipolytic catabolism of cellular fat stores,” Journal of Lipid Research, vol. 50, no. 1, pp. 3–21, 2009.
[11]
T. Okumura, “Role of lipid droplet proteins in liver steatosis,” Journal of Physiology and Biochemistry, vol. 67, no. 4, pp. 629–636, 2011.
[12]
I. Issemann and S. Green, “Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators,” Nature, vol. 347, no. 6294, pp. 645–650, 1990.
[13]
B. M. Forman, J. Chen, and R. M. Evans, “Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors α and δ,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 9, pp. 4312–4317, 1997.
[14]
M. V. Chakravarthy, Z. Pan, Y. Zhu et al., “‘New’ hepatic fat activates PPARα to maintain glucose, lipid, and cholesterol homeostasis,” Cell Metabolism, vol. 1, no. 5, pp. 309–322, 2005.
[15]
R. Ringseis, G. Wen, and K. Eder, “Regulation of genes involved in carnitine homeostasis by PPAR? Across different species (rat, mouse, pig, cattle, chicken, and human),” PPAR Research, vol. 2012, Article ID 868317, 2012.
[16]
A.-M. Engelbrecht, M. Mattheyse, B. Ellis et al., “Proanthocyanidin from grape seeds inactivates the PI3-kinase/PKB pathway and induces apoptosis in a colon cancer cell line,” Cancer Letters, vol. 258, no. 1, pp. 144–153, 2007.
[17]
C. Sánchez-Moreno, G. Cao, B. Ou, and R. L. Prior, “Anthocyanin and proanthocyanidin content in selected white and red wines. Oxygen radical absorbance capacity comparison with nontraditional wines obtained from highbush blueberry,” Journal of Agricultural and Food Chemistry, vol. 51, no. 17, pp. 4889–4896, 2003.
[18]
J. M. Del Bas, J. Fernández-Larrea, M. Blay et al., “Grape seed procyanidins improve atherosclerotic risk index and induce liver CYP7A1 and SHP expression in healthy rats,” FASEB Journal, vol. 19, no. 3, pp. 479–481, 2005.
[19]
V. Du Vigneaud and W. G. Karr, “Carbohydrate utilization. Rate of disappearance of D-glucose from the blood,” Journal of Biological Chemistry, vol. 66, no. 1, pp. 281–300, 1925.
[20]
M. Gutt, C. L. Davis, S. B. Spitzer et al., “Validation of the insulin sensitivity index (ISI0,120): comparison with other measures,” Diabetes Research and Clinical Practice, vol. 47, no. 3, pp. 177–184, 2000.
[21]
J. Folch, M. Lees, and G. H. Sloane Stanley, “A simple method for the isolation and purification of total lipides from animal tissues,” The Journal of Biological Chemistry, vol. 226, no. 1, pp. 497–509, 1957.
[22]
A. T. Anitha Nandhini, S. D. Balakrishnan, and C. V. Anuradha, “Taurine improves lipid profile in rats fed a high fructose-diet,” Nutrition Research, vol. 22, no. 3, pp. 343–354, 2002.
[23]
W. Puavilai and D. Laoragpongse, “Is calculated LDL-C by using the new modified Friedewald equation better than the standard Friedewald equation?” Journal of the Medical Association of Thailand, vol. 87, no. 6, pp. 589–593, 2004.
[24]
R. M. Carr, R. T. Patel, V. Rao et al., “Reduction of TIP47 improves hepatic steatosis and glucose homeostasis in mice,” American Journal of Physiology, vol. 302, no. 8, pp. R996–R1003, 2012.
[25]
K. Matsusue, T. Kusakabe, T. Noguchi et al., “Hepatic steatosis in leptin-deficient mice is promoted by the PPARγ target gene Fsp27,” Cell Metabolism, vol. 7, no. 4, pp. 302–311, 2008.
[26]
R. Raghow, C. Yellaturu, X. Deng, E. A. Park, and M. B. Elam, “SREBPs: the crossroads of physiological and pathological lipid homeostasis,” Trends in Endocrinology and Metabolism, vol. 19, no. 2, pp. 65–73, 2008.
[27]
J. Huang, Y. Jia, T. Fu et al., “Sustained activation of PPARα by endogenous ligands increases hepatic fatty acid oxidation and prevents obesity in ob/ob mice,” FASEB Journal, vol. 26, no. 2, pp. 628–638, 2012.
[28]
F. A. Monsalve, R. D. Pyarasani, F. Delgado-Lopez, and R. Moore-Carrasco, “Peroxisome proliferator-activated receptor targets for the treatment of metabolic diseases,” Mediators of Inflammation, vol. 2013, Article ID 549627, 18 pages, 2013.
[29]
T. R. Koves, J. R. Ussher, R. C. Noland et al., “Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance,” Cell Metabolism, vol. 7, no. 1, pp. 45–56, 2008.
[30]
N. D. Oakes, A. Kjellstedt, P. Thalén, B. Ljung, and N. Turner, “Roles of fatty acid oversupply and impaired oxidation in lipid accumulation in tissues of obese rats,” Journal of Lipids, vol. 2013, Article ID 420754, 12 pages, 2013.
