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. Currently, there are no approved treatments for NASH, and it remains a significant unmet medical need.

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-1 and of the lipogenic enzymes Acc, Fas and Scd-1. 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 TGFβ signaling and markers of inflammation and fibrosis in human cell lines.

Taken together, O304 may be developed into novel treatment for NAFLD and NASH.