Silymarin ameliorates fructose induced insulin resistance syndrome by reducing de novo hepatic lipogenesis in the rat.
High dietary fructose causes insulin resistance syndrome (IRS), primarily due to simultaneous induction of genes involved in glucose, lipid and mitochondrial oxidative metabolism. The present study evaluates effect of a hepatoprotective agent, silymarin (SYM) on fructose-induced metabolic abnormalities in the rat and also assessed the associated thrombotic complications. Wistar rats were kept on high fructose (HFr) diet throughout the 12-week study duration (9 weeks of HFr feeding and subsequently 3 weeks of HFr plus SYM oral administration [once daily]). SYM treatment significantly reduced the HFr diet-induced increase expression of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α/β, peroxisome proliferator-activated receptor (PPAR)-α, forkhead box protein O1 (FOXO1), sterol regulatory element binding protein (SREBP)-1c, liver X receptor (LXR)-β, fatty acid synthase (FAS) and PPARγ genes in rat liver. SYM also reduced HFr diet mediated increase in plasma triglycerides (TG), non-esterified fatty acids (NEFA), uric acid, malondialdehyde (MDA), total nitrite and pro-inflammatory cytokines (C-reactive protein [CRP], interleukin-6 [IL-6], interferon-gamma [IFN-γ] and tumor necrosis factor [TNF]) levels. Moreover, SYM ameliorated HFr diet induced reduction in glucose utilization and endothelial dysfunction. Additionally, SYM significantly reduced platelet activation (adhesion and aggregation), prolonged ferric chloride-induced blood vessel occlusion time and protected against exacerbated myocardial ischemia reperfusion (MI-RP) injury. SYM treatment prevented HFr induced mRNA expression of hepatic PGC-1α/β and also its target transcription factors which was accompanied with recovery in insulin sensitivity and reduced propensity towards thrombotic complications and aggravated MI-RP injury.
Pharmacology Division, CSIR-Central Drug Research Institute, 1 M.G. Marg, Lucknow 226001, U.P, India.
Prem
P
Prakash
Pharmacology Division, CSIR-Central Drug Research Institute, 1 M.G. Marg, Lucknow 226001, U.P, India.
Vishal
V
Singh
Pharmacology Division, CSIR-Central Drug Research Institute, 1 M.G. Marg, Lucknow 226001, U.P, India.
Manish
M
Jain
Pharmacology Division, CSIR-Central Drug Research Institute, 1 M.G. Marg, Lucknow 226001, U.P, India.
Minakshi
M
Rana
Pharmacology Division, CSIR-Central Drug Research Institute, 1 M.G. Marg, Lucknow 226001, U.P, India.
Vivek
V
Khanna
Pharmacology Division, CSIR-Central Drug Research Institute, 1 M.G. Marg, Lucknow 226001, U.P, India.
Manoj Kumar
MK
Barthwal
Pharmacology Division, CSIR-Central Drug Research Institute, 1 M.G. Marg, Lucknow 226001, U.P, India. Electronic address: madhu_dikshit@cdri.res.in.
Madhu
M
Dikshit
D000284:Administration, Oral; D000818:Animals; D015415:Biomarkers / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004334:Drug Administration Schedule; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D005632:Fructose; D005786:Gene Expression Regulation / Q000187:drug effects; D007333:Insulin Resistance / Q000235:genetics; D050155:Lipogenesis / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000097:blood / Q000517:prevention & control; D018384:Oxidative Stress / Q000187:drug effects; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D012838:Silymarin / Q000008:administration & dosage / Q000494:pharmacology*; D013927:Thrombosis / Q000097:blood / Q000517:prevention & control; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects
D015415:Biomarkers; D012838:Silymarin; D005632:Fructose
Fatty liver diseases; Fructose diet; Hepatic de novo lipogenesis; Insulin resistance syndrome; Myocardial ischemia reperfusion injury; Silymarin