PPARα regulates gluconeogenesis and glucose homeostasis independent of CYP2A. More severe glucose and pyruvate intolerance in P+/A- mice than in P-/A- mice suggests that CYP2A regulates glucose homeostasis via PPARα. Both P-/A- mice and P-/A+ mice exhibited comparable higher serum free fatty acids, lower serum β-hydroxylbutyrate, and lower serum glucose (glucose tolerance and gluconeogenesis), but only P-/A- mice revealed a more pronounced fatty liver, suggesting that PPARα-regulated lipid metabolism and gluconeogenesis are prime factors for the development of severe fatty liver in P-/A- mice, and CYP2A deficiency can enhance the PPARα deficiency-related steatosis. PPARα was upregulated in cyp2a5−/− mice (ref.11–12). Thus, elevation of PPARα in cyp2a5−/− mice might be a compensatory response to improve the impaired metabolism capacity caused by the deletion of CYP2A. Further deletion of PPARα in cyp2a5−/− mice causes de-compensation and induces severe fatty liver.
