Fatty acid regulation of hepatic gene transcription

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 alpha, 13, gamma 1, and gamma 2), sterol regulatory element binding protein-1c (SREBP-1c), hepatic nuclear factors (HNF-4 alpha and gamma), retinoid X receptor (RXR alpha), liver X receptor (LXR alpha), and others. In vivo studies established that PPAR alpha- and SREBP-1c-regulated genes are key targets for PUFA control of hepatic gene expression. PUFA activate PPARa 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 PPARa 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 alpha or SREBP-1c. Together, these mechanisms control hepatic lipid composition and affect whole-body lipid composition.