Hepatocyte-specific, PPAR?-regulated mechanisms to promote steatosis in adult mice.

ABSTRACT: Peroxisome proliferator-activated receptor ? (PPAR?) is the target for thiazolidinones (TZDs), drugs that improve insulin sensitivity and fatty liver in humans and rodent models, related to a reduction in hepatic de novo lipogenesis (DNL). The systemic effects of TZDs are in contrast to reports suggesting hepatocyte-specific activation of PPAR? promotes DNL, triacylglycerol (TAG) uptake and fatty acid (FA) esterification. As these hepatocyte-specific effects of PPAR? could counterbalance the positive therapeutic actions of systemic delivery of TZDs, the current study used a mouse model of adult-onset, liver (hepatocyte)-specific PPAR? knockdown (aLivPPAR?kd). This model has advantages over existing congenital knockout models, by avoiding compensatory changes related to embryonic knockdown, thus better modeling the impact of altering PPAR? on adult physiology, where metabolic diseases most frequently develop. The impact of aLivPPAR?kd on hepatic gene expression and endpoints in lipid metabolism was examined after 1 or 18 weeks (Chow-fed) or after 14 weeks of low- or high-fat (HF) diet. aLivPPAR?kd reduced hepatic TAG content but did not impact endpoints in DNL or TAG uptake. However, aLivPPAR?kd reduced the expression of the FA translocase (Cd36), in 18-week Chow- and HF-fed mice, associated with increased NEFA after HF feeding. Also, aLivPPAR?kd dramatically reduced Mogat1 expression, that was reflected by an increase in hepatic monoacylglycerol (MAG) levels, indicative of reduced MOGAT activity. These results, coupled with previous reports, suggest that Cd36-mediated FA uptake and MAG pathway-mediated FA esterification are major targets of hepatocyte PPAR?, where loss of this control explains in part the protection against steatosis observed after aLivPPAR?kd.

SUBMITTER: Wolf Greenstein A 

PROVIDER: S-EPMC5120553 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature