Fatty acids and gene transcription

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