title: Docosahexaenoic acid (DHA) and hepatic gene transcription.
abstract: The type and quantity of dietary fat ingested contributes to the onset and progression of chronic diseases, like diabetes and atherosclerosis. The liver plays a central role in whole body lipid metabolism and responds rapidly to changes in dietary fat composition. Polyunsaturated fatty acids (PUFA) play a key role in membrane composition and function, metabolism and the control of gene expression. Certain PUFA, like the n-3 PUFA, enhance hepatic fatty acid oxidation and inhibit fatty acid synthesis and VLDL secretion, in part, by regulating gene expression. Our studies have established that key transcription factors, like PPARalpha, SREBP-1, ChREBP and MLX, are regulated by n-3 PUFA, which in turn control levels of proteins involved in lipid and carbohydrate metabolism. Of the n-3 PUFA, 22:6,n-3 has recently been established as a key controller of hepatic lipid synthesis. 22:6,n-3 controls the 26S proteasomal degradation of the nuclear form of SREBP-1. SREBP-1 is a major transcription factor that controls the expression of multiple genes involved fatty acid synthesis and desaturation. 22:6,n-3 suppresses nuclear SREBP-1, which in turn suppresses lipogenesis. This mechanism is achieved, in part, through control of the phosphorylation status of protein kinases. This review will examine both the general features of PUFA-regulated hepatic gene transcription and highlight the unique mechanisms by which 22:6,n-3 impacts gene expression. The outcome of this analysis will reveal that changes in hepatic 22:6,n-3 content has a major impact on hepatic lipid and carbohydrate metabolism. Moreover, the mechanisms involve 22:6,n-3 control of several well-known signaling pathways, such as Akt, Erk1/2, Gsk3beta and PKC (novel or atypical). 22:6,n-3 control of these same signaling pathways in non-hepatic tissues may help to explain the diverse actions of n-3 PUFA on such complex physiological processes as visual acuity and learning.
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI 48824, United States. Donald.Jump@oregonstate.edu
authors.forename: Donald B
authors.initials: DB
authors.lastname: Jump
authors.forename: Daniela
authors.initials: D
authors.lastname: Botolin
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Jinghua
authors.initials: J
authors.lastname: Xu
authors.forename: Olivier
authors.initials: O
authors.lastname: Demeure
authors.forename: Barbara
authors.initials: B
authors.lastname: Christian
mesh_terms: D000818:Animals; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D005786:Gene Expression Regulation; D006019:Glycolysis; D006801:Humans; D050356:Lipid Metabolism; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D014157:Transcription Factors; D004281:Docosahexaenoic Acids