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

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

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 (PPARalpha), we investigated the role of PPARalpha in the induction of these enzymes in response to fasting and their relationship to the development of hepatic steatosis in mice deficient in PPARalpha (PPARalpha(-/-)), peroxisomal fatty acyl-CoA oxidase (AOX(-/-)), and in both PPARalpha and AOX (double knock-out (DKO)). Fasting for 48-72 h caused profound impairment of fatty acid oxidation in both PPARalpha(-/-) and DKO mice, and DKO mice revealed a greater degree of hepatic steatosis when compared with PPARalpha(-/-) mice. The absence of PPARalpha in both PPARalpha(-/-) and DKO mice impairs the induction of mitochondrial beta-oxidation in liver following fasting which contributes to hypoketonemia and hepatic steatosis. Pronounced steatosis in DKO 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 PPARalpha and up-regulation of mitochondrial beta-oxidation and microsomal omega-o

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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