N-HMME Upregulates Lipolytic Proteins in the Liver to Counter NAFLD

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a comorbidity associated with diet-induced obesity, diabetes, hyperlipidemia and hypertension. While the prevalence of obesity and its causal role in NAFLD continue to rise, currently, there is no strategy to counter NAFLD. It is the most common liver disease associated with chronic obesity and is one of the top concerns for clinicians as it has the potential to advance into hepatic steatosis, steatohepatitis, and cirrhosis of liver. Recent research suggests that transient receptor potential vanilloid 1 (TRPV1), a non-selective Ca2+ channel protein, is implicated in NAFLD. However, the precise mechanism underlying this remains to be elucidated. TRPV1 activation via dietary supplementation of (E)-N-[(4-hydroxy-3-methoxyphenyl) methyl]-8-methylnon-6-enamide (N-HMME; also known as capsaicin) is an emerging strategy to counter NAFLD. Protein assays from liver lysates in dietary induced obesity models indicate that high fat diet (HFD; 60% of total calories) promoted hepatic steatosis. HFD feeding caused increase in liver weight, downregulated the expression of lipolytic genes and increased triglyceride levels in blood. N-HMME supplementation prevented hepatic steatosis by increasing lipolytic genes while decreasing de novo lipogenesis of fatty acids in the liver. N-HMME increased the expression of lipolytic proteins PPARα, PGC-1α and SiRT-1 and suppressed the expression of lipogenic SCD-1 in the liver. N-HMME significantly prevented hepatic steatosis and decreased circulating triglyceride levels in blood. N-HMME supplementation also suppressed HFD-induced hypertension, hyperglycemia and improved blood glucose handling. Further, N-HMME facilitated the activation of SiRT-1 via Ca2+/Calmodulin dependent protein kinase II dependent mechanism and increased the interaction between SiRT-1 and PPARα. However, N-HMME did not prevent NAFLD in mice, which genetically lack the expression of TRPV1. Our data provide evidence for the emergence of N-HMME as a new drug molecule to counter NAFLD and its associated pathologies.