A critical role for the peroxisome proliferator-activated receptor α (PPARα) in the cellular fasting response: The PPARα-null mouse as a model of fatty acid oxidation disorders

TLDR

The study hypothesizes that PPARα is essential for the cellular metabolic response to fasting. In PPARα‑deficient mice, short‑term fasting causes hepatic steatosis, myocardial lipid accumulation, hypoglycemia, and a blunted ketogenic response, with failure to induce PPARα target genes, mirroring human fatty‑acid oxidation disorders and establishing the knockout mouse as a model.

Abstract

We hypothesized that the lipid-activated transcription factor, the peroxisome proliferator-activated receptor α (PPARα), plays a pivotal role in the cellular metabolic response to fasting. Short-term starvation caused hepatic steatosis, myocardial lipid accumulation, and hypoglycemia, with an inadequate ketogenic response in adult mice lacking PPARα (PPARα −/− ), a phenotype that bears remarkable similarity to that of humans with genetic defects in mitochondrial fatty acid oxidation enzymes. In PPARα +/+ mice, fasting induced the hepatic and cardiac expression of PPARα target genes encoding key mitochondrial (medium-chain acyl-CoA dehydrogenase, carnitine palmitoyltransferase I) and extramitochondrial (acyl-CoA oxidase, cytochrome P450 4A3) enzymes. In striking contrast, the hepatic and cardiac expression of most PPARα target genes was not induced by fasting in PPARα −/− mice. These results define a critical role for PPARα in a transcriptional regulatory response to fasting and identify the PPARα −/− mouse as a potentially useful murine model of inborn and acquired abnormalities of human fatty acid utilization.