Defect in peroxisome proliferator-activated receptor α-inducible fatty acid oxidation determines the severity of hepatic steatosis in response to fasting

Fasting causes lipolysis in adipose tissue leading to the release of large quantities of free fatty acids into circulation that reach the liver where they are metabolized to generate ketone bodies to serve as fuels for other tissues. Since fatty acid-metabolizing enzymes in the liver are transcriptionally regulated by peroxisome proliferator-activated receptor alpha (PPAR alpha), we investigated the role of PPAR alpha in the induction of these enzymes in response to fasting and their relationship to the development of hepatic steatosis in mice deficient in PPAR alpha (PPAR alpha(-/-)), peroxisomal fatty acyl-CoA oxidase (AOX(-/-)), and in both PPAR alpha and AOX (double knockout (DKO)), Fasting for 48-72 h caused profound impairment of fatty acid oxidation in both PPAR alpha(-/-) and DKO mice, and DKO mice revealed a greater degree of hepatic steatosis when compared with PPAR alpha(-/-) mice. The absence of PPAR alpha in both PPAR alpha(-/-) and DKO mice impairs the induction of mitochondrial beta-oxidation in liver following fasting which contributes to hypoketonemia and hepatic steatosis, Pronounced steatosis in DRO mouse livers is due to the added deficiency of peroxisomal beta-oxidation system in these animals due to the absence of AOX. In mice deficient in AOX alone, the sustained hyperactivation of PPAR alpha and up-regulation of mitochondrial beta-oxidation and microsomal omega-oxidation systems as well as the regenerative nature of a majority of hepatocytes containing numerous spontaneously proliferated peroxisomes, which appear refractory to store triglycerides, blunt the steatotic response to fasting. Starvation for 48-72 h caused a decrease in PPAR alpha hepatic mRNA levels in wild type mice, with no perceptible compensatory increases in PPAR gamma and PPAR delta mRNA levels. PPAR gamma and PPAR delta hepatic mRNA levels were lower in fed PPAR alpha(-/-) and DKO mice when compared with wild type mice, and fasting caused a slight increase only in PPAR gamma levels and a decrease in PPAR delta levels. Fasting did not change the PPAR isoform levels in AOX(-/-) mouse liver. These observations point to the critical importance of PPAR alpha in the transcriptional regulatory responses to fasting and in determining the severity of hepatic steatosis.