Nonalcoholic Steatosis and Steatohepatitis. I. Molecular mechanism for polyunsaturated fatty acid regulation of gene transcription

This review addresses the hypothesis that polyunsaturated fatty acids (PUFA ), particularly those of the n-3 family, play pivotal roles as "fuel partit ioners" in that they direct fatty acids away from triglyceride storage and toward oxidation and they enhance glucose flux to glycogen. In doing this, PUFA may reduce the risk of enhanced cellular apoptosis associated with exc essive cellular lipid accumulation. PUFA exert their beneficial effects by upregulating the expression of genes encoding proteins involved in fatty ac id oxidation while simultaneously downregulating genes encoding proteins of lipid synthesis. PUFA govern oxidative gene expression by activating the t ranscription factor peroxisome proliferator-activated receptor-alpha. PUFA suppress lipogenic gene expression by reducing the nuclear abundance and DN A binding affinity of transcription factors responsible for imparting insul in and carbohydrate control to lipogenic and glycolytic genes. In particula r, PUFA suppress the nuclear abundance and expression of sterol regulatory element binding protein-1 and reduce the DNA binding activities of nuclear factor Y, stimulatory protein 1, and possibly hepatic nuclear factor-4. Col lectively, the studies discussed suggest that the fuel "repartitioning" and gene expression actions of PUFA should be considered among the criteria us ed in defining the dietary needs of n-6 and n-3 fatty acids and in establis hing the dietary ratio of n-6 to n-3 fatty acids needed for optimum health benefit.