Fatty Acid Regulation of Hepatic Gene Transcription

Abstract

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 (PPARalpha, beta, gamma1, and gamma2), sterol regulatory element binding protein-1c (SREBP-1c), hepatic nuclear factors (HNF-4alpha and gamma), retinoid X receptor (RXRalpha), liver X receptor (LXRalpha), and others. In vivo studies established that PPARalpha- and SREBP-1c-regulated genes are key targets for PUFA control of hepatic gene expression. PUFA activate PPARalpha 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 PPARalpha 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 PPARalpha or SREBP-1c. Together, these mechanisms control hepatic lipid composition and affect whole-body lipid composition.

Fat metabolism is regulated by altered gene expression of lipogenic enzymes and regulatory factors in liver and adipose tissue but not in semimembranosus muscle of pigs during the fattening period

“…Polyunsaturated fatty acids (n-6 and n-3 FA), and especially long PUFA which are abundant in pigs fed FO, are known to be potent regulators of gene expression (Xu et al, 2002;Jump et al, 2005). The increase in D6D could be expected given its role in the synthesis of C18:3n-6 and long-chain PUFA like C20:4n-6, and may explain the positive correlation with the tissue content of these two FA.…”

ELOVL2 overexpression enhances triacylglycerol synthesis in 3T3‐L1 and F442A cells

“…Lipogenic pathways for TAG synthesis are transcriptionally regulated by sterol regulatory element-binding protein (SREBP)-1c and peroxisome proliferator-activated receptor (PPAR)-c, where various PUFAs are known to regulate the function of these transcriptional factors [20,32,33]. We examined the expression levels of these target genes in established cell lines.…”

“…As to catabolic effects, nÀ3PUFAs are reported to induce FA-oxidation through the action of PPAR-a [20]. Overexpression of a PUFA elongase ELOVL2 in cells was therefore expected to accelerate cellular catabolism.…”

“…An nÀ6 PUFA, arachidonic acid (AA, C20:4nÀ6) is the precursor of the highly inflammatory prostaglandin E2, whereas nÀ3 PUFAs such as eicosapentaenoic acid (EPA, C20:5nÀ3) become the low inflammatory prostaglandin E3 [19]. In the liver, nÀ3 PUFAs are known to catabolize FA by functioning as ligands for PPAR-a [20]. Despite the extensive knowledge on other enzymes, few reports are available as to the function of ELOVL members in PUFA synthesis pathways.…”

Recent advances in the regulation of milk fat synthesis

“…The regulation of lipid synthesis and the role of long-chain PUFA in this regulation have been extensively studied in rodent models and cell culture systems, especially hepatocyte-based systems (see reviews by Duplus and Forest, 2002;Jump et al, 2005;Sampath and Ntambi, 2005). These investigations have provided insight that may be applicable to the mechanism by which biohydrogenation intermediates regulate milk fat synthesis.…”