title: Swertiamarin ameliorates oleic acid induced lipid accumulation and oxidative stress by attenuating gluconeogenesis and lipogenesis in hepatic steatosis.
abstract: Swertiamarin, a bitter secoiridoid glycoside, is an antidiabetic drug with lipid lowering activity meliorates insulin resistance in Type 2 Diabetes condition. Therefore, the study was designed to explore the antioxidant and hypolipidemic activity of swertiamarin in ameliorating NAFLD caused due to hepatic lipid accumulation, inflammation and insulin resistance. Steatosis was induced in HepG2 cells by supplementing 1mM oleic acid (OA) for 24h which was marked by significant accumulation of lipid droplets. This was determined by Oil Red O (ORO) staining and triglyceride accumulation. Swertiamarin (25μg/ml) decreased triglyceride content by 2 folds and effectively reduced LDH release (50%) activity by protecting membrane integrity thus, preventing apoptosis evidenced by reduced cleavage of Caspase 3 and PARP1. We observed that swertiamarin significantly increased the expressions of major insulin signaling proteins like Insulin receptor (IR), PI(3)K, pAkt with concomitant reduction in p307 IRS-1. AMPK was activated by swertiamarin action, thus restoring insulin sensitivity in hepatocytes. In addition, qPCR results confirmed OA up-regulated Sterol Regulatory Element Binding Protein (SREBP)-1c and fatty acid synthase (FAS), resulting in increased fatty acid synthesis. Swertiamarin effectively modulated PPAR-α, a major potential regulator of carbohydrate metabolism which, in turn, decreased the levels of the gluconeogenic enzyme PEPCK, further restricting hepatic glucose production and fatty acid synthesis. Cumulatively, swertiamarin targets potential metabolic regulators AMPK and PPAR-α, through which it regulates hepatic glycemic burden, fat accumulation, insulin resistance and ROS in hepatic steatosis which emphasizes clinical significance of swertiamarin in regulating metabolism and as a suitable candidate for treating NAFLD.
authors.affiliation: Molecular Endocrinology and Stem Cell Research Laboratory, Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara 390002, Gujarat, India. Electronic address: tusharr05@hotmail.com.
authors.forename: Tushar P
authors.initials: TP
authors.lastname: Patel
authors.affiliation: Molecular Endocrinology and Stem Cell Research Laboratory, Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara 390002, Gujarat, India.
authors.forename: Komal
authors.initials: K
authors.lastname: Rawal
authors.affiliation: Molecular Endocrinology and Stem Cell Research Laboratory, Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara 390002, Gujarat, India.
authors.forename: Sanket
authors.initials: S
authors.lastname: Soni
authors.affiliation: Molecular Endocrinology and Stem Cell Research Laboratory, Department of Biochemistry, Faculty of Science, The M.S. University of Baroda, Vadodara 390002, Gujarat, India. Electronic address: sglmescrl@gmail.com.
authors.forename: Sarita
authors.initials: S
authors.lastname: Gupta
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D005234:Fatty Liver / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D005943:Gluconeogenesis / Q000187:drug effects*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D057888:Iridoid Glucosides / Q000494:pharmacology / Q000627:therapeutic use*; D050155:Lipogenesis / Q000187:drug effects*; D019301:Oleic Acid; D018384:Oxidative Stress / Q000187:drug effects*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology; D011753:Pyrones / Q000494:pharmacology / Q000627:therapeutic use*; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D014280:Triglycerides / Q000378:metabolism
chemical_list: D007328:Insulin; D057888:Iridoid Glucosides; D020011:Protective Agents; D011753:Pyrones; D014280:Triglycerides; D019301:Oleic Acid; C013270:swertiamarin; D011065:Poly(ADP-ribose) Polymerases; D055372:AMP-Activated Protein Kinases; D053148:Caspase 3
keywords: AMPK; Hepatic steatosis; Insulin signaling; Oxidative stress; Swertiamarin