Hepatic PPAR? Is Not Essential for the Rapid Development of Steatosis After Loss of Hepatic GH Signaling, in Adult Male Mice.

ABSTRACT: Our group has previously reported de novo lipogenesis (DNL) and hepatic triglyceride content increases in chow-fed male mice within 7 days of hepatocyte-specific GH receptor knockdown (aLivGHRkd). Here, we report that these changes are associated with an increase in hepatic expression of peroxisome proliferator-activated receptor ? (PPAR?), consistent with previous reports showing steatosis is associated with an increase in PPAR? expression in mice with congenital loss of hepatic GH signaling. PPAR? is thought to be an important driver of steatosis by enhancing DNL, as well as increasing the uptake and esterification of extrahepatic fatty acids (FAs). In order to determine whether hepatic PPAR? is critical for the rapid development of steatosis in the aLivGHRkd mouse model, we have generated aLivGHRkd mice, with or without PPAR? (ie, adult-onset, hepatocyte-specific double knockout of GHR and PPAR?). Hepatic PPAR? was not required for the rapid increase in liver triglyceride content or FA indexes of DNL (16:0/18:2 and 16:1/16:0). However, loss of hepatic PPAR? blunted the rise in fatty acid translocase/CD36 and monoacylglycerol acyltransferase 1 expression induced by aLivGHRkd, and this was associated with a reduction in the hepatic content of 18:2. These results suggest that the major role of PPAR? is to enhance pathways critical in uptake and reesterification of extrahepatic FA. Because FAs have been reported to directly increase PPAR? expression, we speculate that in the aLivGHRkd mouse, the FA produced by DNL enhances the expression of PPAR?, which in turn increases extrahepatic FA uptake, thereby further enhancing PPAR? activity and exacerbating steatosis overtime.

SUBMITTER: Kineman RD 

PROVIDER: S-EPMC4870866 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature