Dietary polyunsaturated fatty acids and hepatic gene expression

Area of Science:

• Biochemistry
• Molecular Biology
• Nutritional Science

Background:

• Dietary polyunsaturated fatty acids (PUFA) significantly alter hepatic gene transcription and lipid metabolism.
• PUFA influence the expression of lipogenic, glycolytic, peroxisomal, and cytochrome P450 enzymes.

Purpose of the Study:

• To elucidate the distinct molecular mechanisms by which dietary PUFA regulate hepatic gene transcription and lipid metabolism.
• To investigate the roles of peroxisome proliferator-activated receptor alpha (PPAR alpha) and prostanoids in PUFA-mediated gene regulation.

Main Methods:

• Utilized PPAR alpha-null mice to assess PPAR alpha-dependent gene induction.
• Employed primary rat hepatocytes and 3T3-L1 adipocytes to study PUFA metabolite signaling.
• Performed transfection analysis of S14CAT fusion genes to identify regulatory regions.

Main Results:

• PPAR alpha is essential for PUFA induction of acyl CoA oxidase (AOX) and CYP4A2, but not for suppression of fatty acid synthase (FAS), S14, or L-pyruvate kinase (L-PK).
• Prostaglandin E2 (PGE2) and 20:4n-6 metabolites suppress FAS, S14, and L-PK mRNA via a Gi/Go-coupled pathway in adipocytes.
• PPAR alpha and prostanoid pathways regulate distinct gene promoter regions, with a third independent pathway also identified.

Conclusions:

• Dietary PUFA regulate hepatic gene transcription via at least three distinct mechanisms: PPAR alpha-dependent, prostanoid-mediated, and a PPAR/prostanoid-independent pathway.
• Hepatic lipid metabolism is regulated by an integration of these multiple PUFA-responsive pathways.