title: Hepatosteatosis in peroxisome deficient liver despite increased β-oxidation capacity and impaired lipogenesis.
abstract: 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 α (PPARα) by using liver-specific Pex5(-/-) mice (L-Pex5(-/-) mice). Surprisingly, steatosis was accompanied both by increased mitochondrial β-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 PPARα, challenging the assumption that PPARα 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 PPARα activation and reduced fatty acid secretion cause hepatosteatosis in peroxisome deficient livers.
authors.affiliation: Laboratory of Cell Metabolism, Department of Pharmaceutical Sciences, K.U.Leuven, B-3000 Leuven, Belgium.
authors.forename: Annelies
authors.initials: A
authors.lastname: Peeters
authors.forename: Johannes V
authors.initials: JV
authors.lastname: Swinnen
authors.forename: Paul P
authors.initials: PP
authors.lastname: Van Veldhoven
authors.forename: Myriam
authors.initials: M
authors.lastname: Baes
mesh_terms: D000818:Animals; D015153:Blotting, Western; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D050155:Lipogenesis / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008817:Mice, Mutant Strains; D020411:Oligonucleotide Array Sequence Analysis; D047493:PPAR alpha / Q000378:metabolism; D020675:Peroxisomes / Q000473:pathology*
chemical_list: D047493:PPAR alpha