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Recent Advances in Nutritional Sciences

Fatty Acid Regulation of Hepatic Gene Transcription^1,2

Departments of Physiology, Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824

³To whom correspondence should be addressed. E-mail: Jump{at}msu.edu.

Dietary fat regulates gene expression by controlling the activity or abundance of key transcription factors. In vitro binding and cell culture studies have identified many transcription factors as prospective targets for fatty acid regulation, including peroxisome proliferator-activated receptors (PPAR, ß, 1, and 2), sterol regulatory element binding protein-1c (SREBP-1c), hepatic nuclear factors (HNF-4 and ), retinoid X receptor (RXR), liver X receptor (LXR), and others. In vivo studies established that PPAR- and SREBP-1c–regulated genes are key targets for PUFA control of hepatic gene expression. PUFA activate PPAR by direct binding, leading to the induction of hepatic fatty acid oxidation. PUFA inhibit hepatic fatty acid synthesis by suppressing SREBP-1c nuclear abundance through several mechanisms, including suppression of SREBP-1c gene transcription and enhancement of proteasomal degradation and mRNA_SREBP1c decay. Changes in intracellular nonesterified fatty acids (NEFA) correlate well with changes in PPAR activity and mRNA_SREBP-1c abundance. Several mechanisms regulate intracellular NEFA composition, including fatty acid transport, acyl CoA synthetases and thioesterases, fatty acid elongases and desaturases, neutral and polar lipid lipases, and fatty acid oxidation. Many of these mechanisms are regulated by PPAR or SREBP-1c. Together, these mechanisms control hepatic lipid composition and affect whole-body lipid composition.

KEY WORDS: • gene transcription • hepatic fatty acid metabolism

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