Abstract 419: Metabocin TM Increases Lipolytic Pathways to Counter High Fat Diet-Induced Non-Alcoholic Fatty Liver Disease

Abstract

Non-alcoholic fatty liver disease (NAFDLD) is a comorbidity of high fat diet-induced obesity. NAFLD leads to steatohepatitis and hepatic steatosis, which progress into cirrhosis and liver cancer. Currently, there is no single strategy to counter NAFLD. In our effort to understand the role of transient receptor potential vanilloid receptor in the pathophysiology of high fat diet-induced, non-alcoholic fatty liver disease, we discovered that mammalian liver expresses transient receptor potential vanilloid 1 protein and that Metabocin TM {( E )- N -[(4-hydroxy-3-methoxyphenyl) methyl]-8-methylnon-6-enamide; also know as capsaicin; an agonist of transient receptor potential vanilloid 1 channel protein} significantly prevented mice from diet-induced NAFLD. Feeding high fat diet (60% calories from fat) for 32 weeks, from the age of 6 weeks until 38 weeks, caused hypertension, hyperglycemia, glucose intolerance and hyper triglyceridemia in the wild type mice and Metabocin TM prevented these effects. Metabocin TM markedly prevented hepatic steatosis and decreased lipid accumulation in the liver. Also, Metabocin TM significantly increased the expression of lipolytic PPAR alpha, PPAR gamma co activator 1 alpha, sirtuin-1 and forkhead box protein 01, while suppressed the expression of lipogenic stearoyl CoA desaturase 1. Further, Metabocin TM increased liver lipolysis, facilitated the activation of sirtuin-1 via Ca 2+ /Calmodulin dependent protein kinase II/AMPK-dependent mechanism and induced an interaction between sirtuin-1 and PPAR alpha. Metabocin TM also increased the expression of lipin-1 (a transcriptional regulator of PPAR alpha) and mitochondrial UCP-1. Our data provide evidence for the emergence of Metabocin TM as a novel drug molecule to antagonize NAFLD and its associated pathologies.