TitleDocosahexaenoic acid (DHA) and hepatic gene transcription.
Publication TypeJournal Article
Year of Publication2008
AuthorsJump, DB, Botolin, D, Wang, Y, Xu, J, Demeure, O, Christian, B
JournalChem Phys Lipids
Volume153
Issue1
Pagination3-13
Date Published2008 May
ISSN0009-3084
KeywordsAnimals, Docosahexaenoic Acids, Gene Expression Regulation, Glycolysis, Humans, Lipid Metabolism, Lipogenesis, Liver, Signal Transduction, Transcription Factors, Transcription, Genetic
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.

DOI10.1016/j.chemphyslip.2008.02.007
Alternate JournalChem. Phys. Lipids
PubMed ID18343222
PubMed Central IDPMC2430187
Grant ListR01 DK043220 / DK / NIDDK NIH HHS / United States
R01 DK043220-15 / DK / NIDDK NIH HHS / United States
R01 DK043220-16 / DK / NIDDK NIH HHS / United States
DK43220 / DK / NIDDK NIH HHS / United States