Dietary polyunsaturated fatty acids and regulation of gene transcription.
Dietary polyunsaturated fatty acids (PUFAs) are a source of energy and structural components for cells. PUFAs also have dramatic effects on gene expression by regulating the activity or abundance of four families of transcription factor, including peroxisome proliferator activated receptor (PPAR) (alpha, beta and gamma), liver X receptors (LXRs) (alpha and beta), hepatic nuclear factor-4 (HNF-4)alpha and sterol regulatory element binding proteins (SREBPs) 1 and 2. These transcription factors play a major role in hepatic carbohydrate, fatty acid, triglyceride, cholesterol and bile acid metabolism. Non-esterified fatty acids or fatty acid metabolites bind to and regulate the activity of PPARs, LXRs and HNF-4. In contrast, PUFAs regulate the nuclear abundance of SREBPs by controlling the proteolytic processing of SREBP precursors, or regulating transcription of the SREBP-1c gene or turnover of mRNA(SREBP-1c). The n3 and n6 PUFAs are feed-forward activators of PPARs, while these same fatty acids are feedback inhibitors of LXRs and SREBPs. Saturated fatty acyl coenzyme A thioesters activate HNF-4 alpha, while coenzyme A thioesters of PUFAs antagonize HNF-4 alpha action. Understanding how fatty acids regulate the activity and abundance of these and other transcription factors will likely provide insight into the development of novel therapeutic strategies for better management of whole body lipid and cholesterol metabolism.
Jump
Donald B
DB
Department of Physiology, Michigan State University, East Lansing, Michigan 48824, USA. jump@msu.edu
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004042:Dietary Fats, Unsaturated / Q000008:administration & dosage*; D005231:Fatty Acids, Unsaturated / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010750:Phosphoproteins / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D004042:Dietary Fats, Unsaturated; D005231:Fatty Acids, Unsaturated; D051557:Hepatocyte Nuclear Factor 4; D000071518:Liver X Receptors; C403128:MLX protein, human; D057093:Orphan Nuclear Receptors; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors