Obesity, insulin resistance, and diabetes are strongly linked to the accumulation of excessive lipids in the liver causing nonalcoholic fatty liver disease (NAFLD). Due to the association with obesity and related metabolic diseases, the prevalence of NAFLD has dramatically increased in the past few decades. NAFLD may progress to Nonalcoholic steatohepatitis (NASH) characterized by inflammatory lesions and fibrosis with a greatly increased risk of risk of developing cirrhosis and hepatocellular carcinoma. PNPLA3 is a lipid droplet-associated protein which gene expression is mediated by SREBP-1c in liver. The PNPLA3(148M) dominant negative variant, is highly prevalent in the general population and causes a large increase in the risk for hepatic triglyceride accumulation (steatosis), inflammation, fibrosis, cirrhosis, and even hepatocellular carcinoma. PNPLA3 (148M) suppresses ATGL activity, the major lipolytic enzyme in liver and fat that is activated AMPK/O304. Currently, there are no approved treatments for NASH including reduction in expression of PNPLA3 (148M), and it remains a significant unmet medical need.
AMPK and NASH: An increasing body of evidence has demonstrated that AMPK activity is repressed during metabolic disorders, including obesity, diabetes and NAFLD. The inhibition of AMPK connects lipid dysregulation to inflammation, liver injury and fibrosis in NAFLD. By suppressing the expression and activity of SREBP-1c AMPK suppress hepatic expression genes encoding enzymes mediating de novo lipogenesis while promoting fatty acid oxidation. Pharmacological activation of AMPK improves NALFD and NASH in both murine and simian models.
O304 and NASH: In diet induced obesity (DIO) in mice, O304 mitigates systemic insulin resistance and reduces fatty liver by reducing hepatic de novo lipogenesis (DNL) and by increasing fatty acid oxidation/plasma b-hydroxybutyrate. Consistently, O304 reduces hepatic mRNA expression of SREBP-1c and of the lipogenic enzymes Acc, Fas and Scd-1 as well as of PNPLA3. O304 also potently increases the hepatic mRNA expression of the soluble IL-1RN that should mitigate IL-1β mediated inflammation. Moreover, in mice fed “NASH-diets” O304 reduces plasma ALT and AST levels indicative of reduced liver injury. O304 also suppresses an increase in spleen weight, suggesting reduced portal hypertension. Moreover, O304 suppresses DNL in primary human hepatocytes and suppresses IL-1β and TGFβsignaling and markers of inflammation and fibrosis in human cell lines. Taken together, O304 may be developed into novel treatment for NAFLD/NASH.