Fatty acids and gene transcription

Abstract

The type and quantity of dietary fat ingested contributes to the onset and progression of chronic diseases, such as diabetes and atherosclerosis. The liver plays a central role in whole-body lipid metabolism and responds rapidly to changes in dietary fat composition. In rodents, n-3 polyunsaturated fatty acids (PUFAs) enhance hepatic fatty acid oxidation and inhibit fatty acid synthesis and very low-density lipoprotein secretion, in part, by regulating key transcription factors, including peroxisome proliferator activated receptor-? (PPAR-?), sterol regulatory element binding protein-1 (SREBP-1), carbohydrate regulatory element binding protein (ChREBP) and Max-like factor X (MLX). These transcription factors control the expression of multiple genes involved in lipid synthesis and oxidation. Changes in PPAR-? target genes correlate well with changes in intracellular non-esterified fatty acids. Insulin stimulates hepatic de novo lipogenesis by rapidly inducing SR EBP-1 nuclear abundance (nSREBP-1). This mechanism is linked to insulin-induced protein kinase B (Akt) and glycogen synthase kinase (Gsk)-3? phosphorylation and inhibition of 26S proteasomal degradation of nSREBP-1. n-3 PUFAs, particularly 22:6 n-3, inhibit lipid synthesis by suppressing nSREBP-1. A major action of 22:6 n-3 is to stimulate the loss of nSREBP-1 through 26S proteasomal and extracellular regulated kinase (Erk)-dependent pathways. 22:6 n-3 is the only n-3 PUFA accumulating in livers of rodents or humans ingesting essential fatty acid-sufficient or n-3 PUFA-enriched diets. As such, 22:6 n-3 is a major feedback regulator of hepatic lipid synthesis. Finally, insulin-stimulated glucose metabolism augments de novo lipogenesis by elevating nuclear levels of ChREBP, a key regulator of glycolytic and lipogenic genes. ChREBP binding to promoters requires MLX. n-3 PUFAs repress expression of the glycolytic gene, L-pyruvate kinase and lipogenic genes by suppressing MLX nu c lear abundance. In summary, n-3 PUFAs control the activity or abundance of several hepatic transcription factors that impact hepatic carbohydrate and lipid metabolism. Recent studies have identified Erk, Gsk-3? and MLX as novel targets of fatty acid-regulated gene expression. Keywords: gene transcription; hepatic fatty acid metabolism