Fatty acid-regulated transcription factors in the liver

Abstract

Fatty acid regulation of hepatic gene transcription was first reported in the early 1990s. Several transcription factors have been identified as targets of fatty acid regulation. This regulation is achieved by direct fatty acid binding to the transcription factor or by indirect mechanisms where fatty acids regulate signaling pathways controlling the expression of transcription factors or the phosphorylation, ubiquitination, or proteolytic cleavage of the transcription factor. Although dietary fatty acids are well-established regulators of hepatic transcription factors, emerging evidence indicates that endogenously generated fatty acids are equally important in controlling transcription factors in the context of glucose and lipid homeostasis. Our first goal in this review is to provide an up-to-date examination of the molecular and metabolic bases of fatty acid regulation of key transcription factors controlling hepatic metabolism. Our second goal is to link these mechanisms to nonalcoholic fatty liver disease (NAFLD), a growing health concern in the obese population.

Figure 1

Overview of fatty acid regulation of hepatic gene transcription.

Figure 2

Pathways for hepatic fatty acid synthesis (FASN). (a) The pathway describes the conversion of dietary glucose to palmitate by de novo lipogenesis; the pathway requires acetyl CoA carboxylase (ACC)-1 and fatty acid synthase. Palmitate (16:0) is a product of de novo lipogenesis but is also derived from the diet. Palmitate is subsequently elongated [fatty acid elongase (Elov)l5 and Elovl6] and desaturated [stearoyl CoA desaturase (SCD)] to form C_16–18 saturated and monounsaturated (ω7 and ω9) fatty acids. (b) The essential fatty acids, linoleic acid (18:2, ω6) and α-linolenic acid (18:3, ω3), are derived from the diet. These fatty acids are desaturated [fatty acid desaturases (FADS)1 and FADS2] and elongated (Elovl2 and Elovl5) to form the major C_20–22 polyunsaturated fatty acids (PUFAs) appearing in cells, i.e., arachidonic acid (ARA; 20:4, ω6) and docosahexaenoic acid (DHA; 22:6, ω3). DHA production requires peroxisomal β-oxidation (p-βOx). C₂₂ PUFAs are retroconverted to C₂₀ PUFAs by p-βOx.

Figure 3

Nutrient and hormonal regulation of sterol regulatory element–binding protein-1c (SREBP-1c) nuclear abundance. The diagram illustrates the levels of control of SREBP-1c, from gene transcription to degradation of the protein. See text for details on sites of control and regulation of SREBP-1c nuclear abundance. Insulin and liver X receptor (LXR) agonist induce (+) SREBP-1c nuclear abundance, whereas unsaturated fatty acids (UFAs), docosahexaenoic acid (DHA), and cholesterol lower (−) SREBP-1c nuclear abundance. Several enzymes are involved in covalently modifying nuclear SREBP-1, including protein kinase A (PKA), glycogen synthase kinase-3β, extracellular receptor kinase-1 or -2 (Erk1/2), or ubiquitin ligase (SCF^Fbw7). Several proteins are also involved in controlling SREBP processing, including insulin-inducible gene (Insig-1 or Insig-2), SREBP coactivating protein (SCAP), site-1 protease (S1P), and site-2 protease (S2P). Abbreviations: GSK-3β, glycogen synthase kinase-3β; mTORC, mammalian target of rapamycin complex; Ubxd8, ubiquitin regulatory X d8; +, induction; -, repression or inhibition; ?, mechanism not defined.

Figure 4

The role of endogenous fatty acid metabolism in the control of hepatic gene transcription. The generation of fatty acids within hepatic parenchymal cells affects the control of at least three transcription factors, peroxisome proliferator-activated receptor α(PPARα), sterol regulatory element–binding protein 1 (SREBP-1), and forkhead box O1 (FoxO1). The mechanisms include the production of fatty acids by de novo lipogenesis (DNL) and monounsaturated fatty acid (MUFA) (18:1, ω7) and polyunsaturated fatty acid (PUFA) (C_20–22 ω3 and ω6 PUFA) synthesis. SREBP-1 nuclear abundance is well suppressed by C_20–22 PUFA, and hepatic conversion of essential fatty acids to C_20–22 PUFA suppresses SREBP-1 nuclear abundance and DNL. Because this pathway produces both C₂₀ and C₂₂ PUFAs, PPARα signaling can be affected. C₂₀ PUFAs, but not C₂₂ PUFAs, are robust activators of PPARα. FoxO1 activity is not affected by exogenous fatty acids or endogenous production of PUFAs. FoxO1 nuclear abundance, however, is regulated by mechanisms that control hepatic conversion of palmitoleic acid (16:1, ω7) to cis-vaccenic acid (18:1, ω7). Increased hepatic production of 18:1, ω7 induces production of rictor, a component of mTORC2. mTORC2 phosphorylates Akt-S⁴⁷³, and active Akt phosphorylates FoxO1-S²⁵⁶. Phospho-FoxO1 is excluded from nuclei and degraded in the proteasome. The outcome is suppressed expression of genes involved in gluconeogenesis (GNG) and hepatic glucose production (HGP). The up ( green) and down (red ) block arrows represent induction or repression of the pathway or transcription factor. Abbreviations: CTE1, cytosolic thioesterase-1; CYP4A, cytochrome P450-4A; Elovl, fatty acid elongase; G6Pase, glucose-6 phosphatase; mRNA, messenger ribonucleic acid; Pck1, phosphoenolpyruvate carboxykinase.