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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.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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, 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 mRNASREBP1c decay. Changes in intracellular nonesterified fatty acids (NEFA) correlate well with changes in PPAR activity and mRNASREBP-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
Dietary fat is an important macronutrient for growth and development of all organisms. It provides substrates for energy metabolism, membranes, and signaling molecules and regulates gene expression. Since the original description of dietary fat as a regulator of gene expression over a decade ago, many transcription factors were identified as prospective targets for fatty acid regulation, including peroxisome proliferator-activated receptors (PPAR, ß, 1, and 2),4 sterol regulatory element binding protein-1c (SREBP-1c), hepatic nuclear factors (HNF-4 and ), retinoid X receptor (RXR), liver X receptor (LXR), and others (1,2). Nonesterified fatty acids (NEFA) bind PPAR (3), HNF4 (4,5), RXR (6), and LXR (7). In this fashion, fatty acids act like hydrophobic hormones to control gene expression. However, fatty acids regulate other transcription factors, such as SREBP-1c and nuclear factor 
B, through indirect mechanisms. Fatty acid control of these transcription factors is less clear.
This review focuses on the (n-3) PUFA control of hepatic PPAR and SREBP-1c. In vivo studies established that multiple PPAR and SREBP-1c target genes are regulated by changes in dietary fat composition. PPAR induces fatty acid oxidation, whereas SREBP-1c induces fatty acid synthesis. This mechanism controls hepatic lipid composition as well as the type and quantity of lipids available for VLDL synthesis and secretion (Fig. 1). Because the liver plays a central role in whole-body lipid metabolism, such regulatory schemes affect whole-body lipid composition and likely contribute to the onset and progression of several chronic diseases, including atherosclerosis, diabetes, and obesity (1).
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NEFA enter cells through transporters [fatty acid transport protein (FATP) or fatty acid transporter CD36 (FAT)] or diffusion (Fig. 1). NEFA are rapidly converted to fatty acyl CoA (FACoA) by FATP (9) or fatty acyl CoA synthetases (10). NEFA and FACoA are bound to fatty acid binding protein (FABP) and acyl CoA binding protein (ACBP), proteins that transport fatty acids to intracellular compartments for metabolism (11) or to the nucleus to interact with transcription factors (12). Cells challenged with exogenous fatty acids rapidly assimilate the fatty acids into neutral and polar lipids; some will be oxidized. These metabolic pathways keep intracellular NEFA and FACoA very low. However, intracellular NEFA can also arise from the hydrolysis of complex lipids by lipases (13) or the hydrolysis of FACoA by thioesterases (14). As discussed below, these pathways play an important role in controlling the availability of lipid mediators regulating transcription factors.
Studies with PPAR null mice, SREBP-1c, and LXR overexpression revealed 3 pathways for (n-3) PUFA control of hepatic gene expression: 1) n-3 PUFA induction of mono- and ß-oxidation requires PPAR; 2) (n-3) PUFA suppression of de novo lipogenesis and monounsaturated fatty acid (MUFA) synthesis requires SREBP-1c; 3) (n-3) PUFA suppression of the glycolytic enzyme, L-pyruvate kinase, does not involve PPAR, SREBP-1c, or LXR (15–18). The (n-3) PUFA function as feed-forward activators of fatty acid oxidation and feedback inhibitors to prevent the production of new fatty acids, including PUFA. This regulatory scheme not only reduces overall hepatic lipid content and VLDL secretion, but also eliminates excessive very long-chain PUFA that may promote oxidant stress or impair membrane integrity.
Fatty Acid Regulation of Hepatic PPAR.
PPAR binds (n-3) PUFA (3) and (n-3) PUFA regulate multiple PPAR target genes in cell culture and in vivo (1,17). If PPARs are sensors of intracellular lipid, then intracellular NEFA should parallel changes in PPAR activity and the abundance of target gene transcripts. Indeed, when hepatocytes are challenged with 20:5(n-3), induction of PPAR target genes, such as cytochrome P450 4A and cytosolic thioesterase I, correlates well with changes in nonesterified 20:5(n-3) (17,19). While challenging hepatocytes with 18:3(n-3) also significantly changes in intracellular non-esterified 18:3(n-3) and complex lipid composition, 18:3(n-3) weakly activates PPAR. Such studies suggest that merely perturbing intracellular NEFA is insufficient to activate PPAR. Several explanations can account for this difference: 1) selective transport of fatty acids to the nucleus and interaction with PPAR; 2) selective recruitment of coactivators by the fatty acid-PPAR/RXR heterodimer; and 3) differential fatty acid metabolism.
Although the first 2 possibilities were not tested, there is reasonable evidence for differential metabolism of 18:3(n-3) and 20:5(n-3) in hepatocytes. C20 PUFA, but not C18 PUFA, are rapidly elongated to C22 PUFA in primary hepatocytes and other cell types (19,20). Elovl-2 and Elovl-5 are the fatty acid elongases that carry out this reaction. These enzymes are components of the pathway that converts dietary 18:2(n-6) and 18:3(n-3) to 20:4(n-6) and 22:6(n-3), the main C20–22 PUFA that accumulate in membranes. The fact that 18:3(n-3) is neither elongated nor desaturated in primary hepatocytes indicates either low 
6 desaturase activity or channeling into other metabolic pathways (Fig. 2).
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activators (19), the addition of C22 PUFA to hepatocytes yields a net gain of 20:5(n-3) in both the esterified and nonesterified lipid fraction of the cell (19). C22 PUFA-CoA are retroconverted to C20 PUFA-CoA in the peroxisome by ß-oxidation (21). Most chain-shortened (ß-oxidized) products are assimilated into neutral or polar lipids. However, lipases acting on complex lipids or thioesterases acting on FACoA generate 20:5(n-3) as a NEFA (Fig. 2). This cycle of fatty acid assimilation into complex lipid and release of NEFA reflects remodeling of membranes and neutral lipids (13) and is likely a sorting mechanism to control cellular lipid composition.
Strong PPAR agonists, such as WY14,643, induce several fatty acid elongases, desaturases, and peroxisomal enzymes, leading to changes in hepatic and blood lipid profiles (18,22,23). The expression of these enzymes is controlled by nutritional, hormonal, developmental, and tissue-specific factors. We anticipate that changes in the activity of these enzymes will affect complex lipid and intracellular NEFA composition, as well as the control of fatty acid–regulated transcription factors.
Are Other Hepatic Nuclear Receptors Regulated by PUFA? LXR.
LXR, but not LXRß, is a target of fatty acid regulation in established cell lines (7,20,24). Although some LXR-regulated gene products such as ATP-binding cassette, sub-family A (ABC1), member 1(ABCA1) and SREBP-1c are downregulated by fatty acids, the mechanisms for control cannot be attributed to fatty acid interference with oxysterol activation of LXR. MUFAs destabilize ABCA1 in cell membranes (25,26), and promoter analyses indicate that the LXR response element (LXRE) in the SREBP-1c promoter is not required for PUFA suppression of SREBP-1c gene transcription (27). These observations, coupled with the absence of PUFA suppression of many LXR-regulated genes in vivo (17) argue against LXR as a target for PUFA control of gene transcription in vivo.
HNF-4.
HNF-4 and bind FACoA, and fatty acids (4,5), and HNF-4 has fatty acyl thioesterase activity (28). HNF-4 controls an extensive network of genes in the liver and other tissues. Of these, few are regulated by dietary PUFA in vivo; exceptions include L-pyruvate kinase, glucose 6-phosphatase, and apolipoproteins A1 and CIII. Our studies suggest that fatty acid control of HNF-4 target genes is promoter specific (unpublished data). As such, factors other than HNF-4 are likely involved in the PUFA control of these genes. Additional studies are required to evaluate the role that fatty acids, fatty acyl CoA, and the newly described thioesterase activity play in the control of HNF-4 and its regulatory network in vivo.
SREBP-1c is a Target for Fatty Acid Control in Liver. Worgall et al. (29) reported that SREBP-1 and SREBP-2 were targets of fatty acid control in established cell lines. Subsequent reports established that only SREBP-1c was a major target of PUFA control in liver (1). SREBP-1c is one of 3 helix loop-helix-basic leucine zipper protein transcription factors (SREBP-1a, SREBP-1c, and SREBP-2) that play a central role in the control of cholesterol and fatty acid synthesis, VLDL assembly, and gluconeogenesis (30,31).
The principal mechanism for SREBP regulation of gene transcription involves control of its nuclear abundance (nSREBP). nSREBP is regulated by 2 post-translational mechanisms, proteolytic processing (31) and proteasomal degradation (32). All SREBPs are synthesized as precursors (pSREBP, 
125 kDa) tethered to the endoplasmic reticulum (ER) and escorted to the Golgi complex by SREBP-cleavage activating protein (SCAP) for proteolytic processing. nSREBP is transported to the nucleus, via importin-ß (33), where it binds sterol regulatory elements in promoters of specific genes, recruits coactivators to the promoter, and stimulates gene transcription (34). Phosphorylation and ubiquitination of nSREBP targets nSREBP for proteasomal degradation (35). Sterols regulate nSREBP levels by controlling the proteolytic processing step, not proteasomal degradation. Sterols induce the ER-resident proteins, Insig-1 and Insig-2, to bind SCAP; this retains the SCAP-SREBP complex in the ER and prevents its cleavage to nSREBP (36). This is the molecular basis for cholesterol suppression of nuclear SREBP-2 abundance and the suppression of endogenous cholesterol synthesis.
Although SREBP-1c and SREBP-2 are structurally similar, their regulation in the liver by nutrients, hormones, and during postnatal development is quite different (Fig. 3). Unlike SREBP-2, SREBP-1c nuclear abundance is controlled by several mechanisms (Fig. 3). Insulin and oxysterols (LXR agonists) induce SREBP-1c gene transcription, elevate nSREBP-1c, and induce de novo lipogenesis (31). Insulin regulates SREBP-1c gene transcription through phosphoinositide 3 kinase (PI3 kinase) and Akt (37) as well as changes in Insig-1 and -2 expression (38). The SREBP-1c promoter contains regulatory elements for LXR, SREBP, NFY, and Sp1. Both LXR agonists and elevated nSREBP stimulate SREBP-1c promoter activity.
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Post-translational mechanisms are the dominant means for controlling nSREBP-1c in neonatal liver (18,40). Suckling rats have ample hepatic nSREBP-2, but essentially no nSREBP-1c. The selective expression of SREBP-2 vs. SREBP-1c in liver nuclei during postnatal development leads to enhanced cholesterol synthesis and suppressed synthesis of saturated (de novo lipogenesis) and monounsaturated fatty acids (9 desaturase and fatty acid elongase-6). The mechanism for the selective elimination of SREBP-1c from the nucleus is linked to low circulating insulin and the ingestion of a high-fat milk diet. Rat milk is deficient in very long-chain PUFA (18). The mechanisms controlling nSREBP-1c in neonatal liver differ from those of the adult. We speculate that diminished insulin stimulation of nSREBP-1c accumulation and enhanced nSREBP-1c proteasomal degradation account for the absence of nSREBP-1c in neonatal liver.
Perspective and Future Studies.
Changes in intracellular NEFA correlate well with the control of both PPAR and SREBP-1c function. The capacity of cells to interconvert fatty acids (Fig. 2) and release these fatty acids as NEFA represents a novel mechanism for the generation of lipid mediators controlling transcription factors. It is reasonable to predict that manipulation of the metabolic pathways that control intracellular NEFA composition will affect fatty acid–regulated transcription factors and their regulatory networks. Pharmacological or genetic targeting of these enzymes is required to evaluate these possibilities. Such studies may reveal novel strategies for the management of hepatic and whole-body lipid composition.
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FOOTNOTES |
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2 Supported by the National Institutes of Health, grant # DK43220, the National Research Initiative of the U.S. Department of Agriculture Cooperative State Research, Education and Extension Service, grant # 2003–5200-3400, and the Michigan Agriculture Experiment Station.
4 Abbreviations used: ABCA1, ATP-binding cassette, sub-family A (ABC1), member 1; ACBP, acyl CoA binding protein; ER, endoplasmic reticulum; FABP, fatty acid binding protein; FACoA, fatty acyl CoA; FAT, fatty acid transporter (CD36); FATP, fatty acid transport protein; HNF-4, hepatic nuclear factor-4; LXR, liver X-receptor; LXRE, LXR response element; MUFA, monounsaturated fatty acid; NEFA, nonesterified fatty acid; PI3 kinase, phosphoinositide 3 kinase; PPAR, peroxisome proliferator-activated receptor; RXR, retinoid X receptor; SCAP, SREBP-cleavage activating protein; SREBP, sterol regulatory element binding protein.
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