Hepatic PUFA content impacts fatty liver in mouse models of obesity & diabetes

Abstract

Non-alcoholic fatty liver disease (NAFLD) has increased in parallel with the incidence of obesity. NAFLD is characterized by abnormal accumulation of hepatic triglycerides, induction of inflammatory markers and reduced levels of hepatic C20-22 PUFA. Two approaches were used to determine if hepatic PUFA content impacts fatty liver & inflammation. LDL-R (−/−) mice fed a high fat-high cholesterol (HFHC) diet become obese and develop fatty liver; hepatic C20-22 PUFA are low while inflammatory markers (nuclear NFkB-p65 and MCP1 & CD68 expression) are induced. Supplementing the HFHC diet with omega-3 C20-22 PUFA prevented fatty liver and inflammation in these obese mice. The second approach used a high fat (lard) diet to induce obesity and diabetes in C57BL/6J mice. These mice develop fatty livers with low levels of C20-22 PUFA and fatty acid elongase-5 (Elovl5). Elovl5 is a key enzyme involved in PUFA synthesis. A recombinant adenovirus approach was used to restore hepatic Elovl5 activity to normal and elevate hepatic C20-22 PUFA content. This treatment restored hepatic triglycerides & nuclear NFkB-p65 content to normal. These studies establish that mechanisms controlling hepatic C20-22 PUFA content play an important role in regulating hepatic triglycerides and inflammation in mouse models of diet-induced fatty liver disease. Research support: NIFA (2009-65200-05846) and NIDDK (DK43220).