Hepatosteatosis in peroxisome deficient liver despite increased β-oxidation capacity and impaired lipogenesis

Peroxisome deficiency in liver causes hepatosteatosis both in patients and in mice. Here, we studied the mechanisms that contribute to this lipid accumulation and to activation of peroxisome proliferator activated receptor alpha (PPAR alpha) by using liver-specific Pex5(-/-) mice (L-Pex5(-/-) mice). Surprisingly, steatosis was accompanied both by increased mitochondrial beta-oxidation capacity, confirming previous observations, and by impaired de novo lipid synthesis mediated by reduced expression of sterol regulatory element binding protein 1c and its targets. As a consequence, when challenged with a high fat diet, L-Pex5(-/-) mice were protected from adiposity. Hepatic fatty acid uptake was strongly increased whereas the expression of apolipoproteins and the lipoprotein assembly factor microsomal triglyceride transfer protein were markedly reduced resulting in reduced secretion of very low density lipoproteins. Most of these changes seemed to be orchestrated by the endogenous activation of PPAR alpha, challenging the assumption that PPAR alpha activation in hepatocytes requires fatty acid synthase dependent de novo fatty acid synthesis. Expression of cholesterol synthesizing enzymes and cholesterol levels were not affected in peroxisome deficient liver. In conclusion, increased fatty acid uptake driven by endogenous PPAR alpha activation and reduced fatty acid secretion cause hepatosteatosis in peroxisome deficient livers. (C) 2011 Elsevier Masson SAS. All rights reserved.