Fatty acids and gene transcription

Donald B Jump,Yun Wang,Barbara Christian,Jinghua Xu,Daniela Botolin

doi:10.3402/fnr.v50i0.1569

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

Highlights

Dietary fat is an important macronutrient for growth and development in all animals
Since the original description of dietary fat as a regulator of gene expression over a decade ago, many transcription factors have been identified as prospective targets for fatty acid regulation, including peroxisome proliferator activated receptor (PPAR; a, b, g1 and g2), sterol regulatory element binding protein-1 (SREBP-1), hepatic nuclear factor-4 (HNF-4; a and g), retinoid X receptor-a (RXR-a), liver-X factor-a (LXR-a), carbohydrate regulatory element binding protein (ChREBP) and Max-like factor X (MLX) (1Á4)
In vivo and cell-culture studies have established that dietary n-3 polyunsaturated fatty acid (PUFA) regulate multiple genes involved in hepatic carbohydrate and lipid metabolism by targeting key transcription factors, i.e. peroxisome proliferator activated receptor-a (PPAR-a), SREBP-1, ChREBP and MLX (3, 10Á15)

Summary

Introduction

Dietary fat is an important macronutrient for growth and development in all animals. Excessive levels of dietary fat or an imbalance of saturated fat versus unsaturated fat or n-6 versus n-3 polyunsaturated fatty acids (PUFAs) have been implicated in the onset and progression of several chronic diseases, including atherosclerosis (coronary artery disease and stroke), diabetes and obesity, cancer, major depressive disorders and schizophrenia [1]. Since the original description of dietary fat as a regulator of gene expression over a decade ago, many transcription factors have been identified as prospective targets for fatty acid regulation, including peroxisome proliferator activated receptor (PPAR; a, b, g1 and g2), sterol regulatory element binding protein-1 (SREBP-1), hepatic nuclear factor-4 (HNF-4; a and g), retinoid X receptor-a (RXR-a), liver-X factor-a (LXR-a), carbohydrate regulatory element binding protein (ChREBP) and Max-like factor X (MLX) (1Á4). Fatty acids control the nuclear abundance of key transcription factors, such as SREBP-1, nuclear factor-kB, ChREBP and MLX [1, 3, 4].

Results

Conclusion