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also been suggested to mediate glucose-induced expression of FAS as well as other hepatic genes (Fig. 1.5).4148 An upstream stimulatory factor (USF)-bind-ing site at +292/+297 bp in the first intron was reported to be a positive regulatory element involved in glucose responsiveness of the FAS gene.49

Glucose-6-phosphate has been postulated to be the signaling molecule mediating glucose/insulin stimulation of several lipogenic genes including pyruvate kinase, spot 14, and FAS.5051 However, xyulose 5-phosphate, an intermediate in the pentose phosphate pathway, is also suggested to play this role.50 Additionally, stimulation of FAS and S14 mRNA levels by glucose and xylitol in rat hepatocyte cultures is more closely correlated with changes in intracellular glucose 6-phosphate levels than xylulose 5-phosphate levels, supporting the hypothesis that glucose 6-phosphate is likely the critical metabolite for regulation of lipogenic gene expression by glucose.51,52 However, the signaling pathway subsequent to glucose/glucose metabolites which mediate the transcriptional effects on gene expression, is still poorly understood. Glucose response-binding protein (GRBP) binds to the CACGTG motif of the glucose response element and has been identified as a transcription factor mediating the effects of glucose (Fig. 1.5). This protein is activated by high glucose concentrations in vivo.50 Furthermore, the DNA-binding activity of GRBP was found to be inhibited by low glucose concentrations in vivo and by cAMP in cultured hepatocytes.50

1.9 Regulatory Effects of Polyunsaturated Fatty Acids

Polyunsaturated fatty acids of the n-3 and n-6 families are known to suppress hepatic mRNA levels of several lipogenic genes, including FAS.53 With the exception of glucose-6-phosphate dehydrogenase, PUFAs exert their regulatory effects at the level of transcription.53 PUFAs exert dominant negative effects on many of the genes of lipogenesis and are known to override the stimulatory effects of insulin, carbohydrates, and thyroid hormones. Furthermore, the direct effects of PUFAs on the liver do not require extrahepatic factors.

PUFAs are known to suppress hepatic gene expression through three distinct pathways: (1) a peroxisome proliferator activated receptor (PPAR)-dependent pathway, (2) a prostanoid pathway, and (3) a PPAR and pros-tanoid-independent pathway. Although fibrates and prostanoids have modest inhibitory effects on FAS gene expression, the PUFA-mediated suppression of this gene in the liver does not require either PPARa activation or cyclooxygenase conversion of PUFA to eicosanoids (Fig. 1.6).54-56 However, the n-6 PUFA arachidonic acid inhibits several lipogenic genes, including FAS in 3T3-L1 adipocytes, through a prostanoid pathway.57 Furthermore, cyclooxygenase products from non-parenchymal cells can act on parenchy-mal cells through a paracrine process and mimic the effect of n-6 PUFAs on lipogenic gene expression.57

Adipocytes Parenchymal Cell

Adipocytes Parenchymal Cell

Proposed mechanism of polyunsaturated fatty acid regulation of the hepatic fatty acid synthase gene. FAS: fatty acid synthase, PGF2a: prostaglandin F2-a, PGE2: prostaglandin E2, COX: cyclooxygenase, 20:4n-6: arachidonic acid, SREBP1: sterol response element binding protein.

Several labs have investigated the mechanisms of PUFA regulation of FAS gene expression. Feeding PUFAs resulted in a decrease in the mature form of SREBP-1 in liver nuclei, which paralleled changes in FAS and ACC mRNA in wild-type mice. Studies using transgenic mice confirmed that the suppres-sive effect of PUFAs on hepatic FAS expression is due to a decrease in the mature form of SREBP-1 protein.58 Other labs have also demonstrated the suppressive effects of dietary PUFAs on SREBP-1 expression mediate the subsequent regulation of FAS expression.59,60 This has been confirmed by feeding fish oils, which downregulate the mature form of SREBP by decreasing SREBP-1c mRNA expression and leads to the concomitant decrease in hepatic FAS mRNA.61,62 Studies using cultured hepatocytes linked fatty acid peroxidation to the effects of PUFAs on gene expression.63 These findings suggest that the in vivo inhibitory effects of PUFAs on lipogenic genes could be mediated indirectly by a peroxidative mechanism. Further studies will be necessary to explore this signaling pathway in the liver.

1.10 Effects of Glucagon and cAMP

Fasting increases glucagon levels, which may contribute to downregulation of lipogenesis. Insulin presumably mediates the marked increase in the rate of FAS transcription that occurs subsequent to refeeding fasted animals. This elevation can be completely blocked by administration of glucagon or dibu-tyryl cAMP during the refeeding period. This implies that glucagon, via its second messenger cAMP, antagonizes the stimulatory effects of insulin on

FAS expression.21 In support of this theory, in vitro studies using H4IIE hepatoma cells demonstrate that glucagon antagonizes the effect of insulin on FAS transcription by increasing intracellular levels of cAMP. Studies using the H4IIE hepatoma cell line with a CAT-linked FAS promoter, demonstrate that cAMP is an effective inhibitor of insulin-stimulated FAS transcription.20 Progressive deletions of sequences from the FAS 5'-flanking region led to identification of a cAMP response element between -149 and +68. The FAS IRS was required for cAMP antagonism of insulin action.16 An inverted CCAAT box was subsequently identified in the -99/-92 region of the FAS gene. Mutations in this region abolished cAMP responsiveness, suggesting this region is also responsible for mediating the effects of cAMP. Consistent with the localization of the FAS IRS to the -68/-52 bp region, insulin responsiveness was not affected by mutations in the -99/-92 region.20 The identification of the cAMP response sequence of FAS as an inverted CCAAT box puts the FAS gene in a small group of cAMP-regulated genes that do not use the more common CREB- or ATF-1-binding sites for transcriptional regulation. In fact, the basal transcription factor NF-Y and related proteins bind to the inverted CCAAT box of the FAS promoter in vitro.64

1.11 Regulatory Effects of Thyroid Hormones

In addition to changes in the levels of circulating insulin and glucagon, thyroid hormone (T3) is also elevated during refeeding of fasted animals. Thyroid hormone stimulates FAS expression through a mechanism that is independent of insulin. Administration of thyroid hormone to rats for 7 days doubled FAS activity in liver.65 Furthermore, hypothyroidism reduced hepatic FAS activity.66 These effects can be demonstrated in vitro as well. FAS activity can be stimulated 2- to 3-fold in primary cultures of rat and chick embryo hepatocytes.67-69 This is due to an increase in gene transcription and is accompanied by a 5-fold increase in FAS mRNA.

Adipocytes have also been demonstrated to be responsive to T3.69 When mature 3T3-L1 adipocytes were treated with 10 nM T3, the relative rate of FAS synthesis, the steady-state mRNA level, and the transcriptional rate all increased within hours and could be sustained at this level for 24 h.69 Thyroid hormone exerts its effects on FAS transcription by heterodimeriza-tion of ligand-bound thyroid hormone receptor (TR) with the retinoid receptor, RXR. The TR/RXR heterodimer binds to the consensus thyroid hormone response element (TRE) and promotes gene transcription.70-72 Transfections of fusion constructs of the human FAS promoter linked to the luciferase reporter gene into cultured human cells have identified two TREs, TRE1 (GGGTTAcgtcCGGTCA at -716 to -731) and TRE2 (sequence GGGTCC, at -117 to -112).73

1.12 Insulin-Like Effects of Angiotensin II

In addition to its synthesis in the classical renin angiotensin system, the hypertensive hormone angiotensin II (AII) is secreted from adipose tis-sue.74,75 In adipocytes, AII has an insulin-like effect and acts as a lipogenic hormone to increase fatty acid and triglyceride synthesis.76 We have demonstrated that AII increases FAS enzyme activity and mRNA content by upregulating FAS gene transcription.76 Recently, in an attempt to identify AII regulatory sequences in the FAS gene, we found that AII targets insulin regulatory sequences that were previously identified28 as E-box motifs.30 Furthermore, we found that ADD1 is a potential transcription factor mediating transcriptional regulation of the FAS gene by AII.77

1.13 Regulatory Effects of the Obesity Genes 1.13.1 Leptin

Leptin, the ob gene product, is a protein specifically secreted from adipose tissue, and is transported to the hypothalamus where it binds specific receptors resulting in a decrease in appetite.78,79 Since its identification, leptin has been recognized as a hormone which induces satiety and increases basal energy expenditure. Food intake, specifically dietary carbohydrate, results in the rapid and specific induction of ob mRNA levels in rat adipose tissue.80,81 The effects of leptin on FAS may be mediated by glucose, polyunsaturated fatty acids, or both. Administration of leptin to rats consuming a high-carbohydrate, fat-free diet suppressed the mRNA expression for several lipogenic enzymes compared to rats consuming a diet rich in corn oil. Corn oil, which is rich in polyunsaturated fatty acids, suppressed lipogenic enzyme expression while concomitantly increasing leptin expression.79

Using hepatocytes and adipocytes from Wistar fatty rats, Fukuda et al.82 investigated the transcriptional regulation of the FAS gene by insulin/glucose, PUFAs, and leptin, and compared them to lean controls. The region of -57/-35 of the FAS gene, which has previously been identified as insulin responsive, was linked to the CAT-reporter gene containing a heterologous promoter and transfected into these cells.28,82 In the presence of insulin, there was marked stimulation of reporter gene activity in hepatocytes from lean rats, but there was not a significant increase in hepatocytes from obese rats. Stimulation of the reporter gene by insulin was reduced in leptin-treated cells and in cells from lean rats containing an expression vector encoding leptin. However, leptin-treated cells from obese rats did not respond to insulin.

These effects were mediated by leptin-dependent reductions in the insulin-binding capacities of the hepatic and adipose tissue receptors.82

1.13.2 Agouti

Agouti is a paracrine factor normally secreted within hair follicles during the neonatal hair growth period. However, this hormone is also expressed in human adipose tissue,83 suggesting its possible involvement in lipid and energy metabolism. The mechanism of the action of this hormone in both coat color and weight regulation is discussed in detail by Zemel et al. in Chapter 10 of this book. We will discuss only the transcriptional effects of agouti on the FAS gene.

We have demonstrated that agouti acts on adipocytes to increase lipogenesis via a calcium-dependent mechanism.84 Obese viable yellow mice which overexpress the agouti protein have significantly elevated levels of intracellular calcium and FAS gene expression compared to normal mice.85 Furthermore, results from these studies determined that treatment of these animals with the calcium channel blocker, nifedipine, resulted in a dramatic increase in adipose FAS activity. This effect may be due, in part, to reduced plasma insulin levels in the nifedipine-treated viable yellow mice.85 To test the possibility that increased FAS activity in adipose tissue of obese viable yellow mice was due to the direct effects of agouti, Jones et al. treated 3T3-L1 adipocytes in vitro with recombinant agouti protein.86 Agouti treatment resulted in a 1.5-fold increase in FAS mRNA levels. In addition, FAS activity and triglyceride content were 3fold higher in agouti-treated 3T3-L1 cells relative to controls. These effects were attenuated by simultaneous treatment with nifedipine. Together these data demonstrate that the agouti protein can directly increase lipogenesis in adipo-cytes via a calcium dependent mechanism.86 Furthermore, we have identified an agouti-responsive region at the -435/-415 in the FAS promoter which is upstream of the previously identified insulin-responsive E-box.87

1.14 Regulation of the FAS Gene by Other Factors

Like glucagons and cAMP, growth hormone (GH) decreases FAS mRNA abundance by decreasing both gene transcription and mRNA stability.88,89 GH-mediated inhibition of lipogenesis in adipocytes of growing pigs was due to decreased insulin sensitivity.90 However, GH did not alter early events in the insulin signaling cascade, such as receptor binding and receptor kinase activation, suggesting that GH alters insulin signaling downstream of receptor activation.90

Other nutrients, including dietary protein and minerals, regulate FAS gene expression. Hepatic FAS mRNA abundance in Wistar fatty rats was significantly lower after feeding soybean protein compared to feeding casein.91 The regulation of FAS by essential amino acids was also reported in HepG2 cells.92 A de ficiency of dietary copper is accompanied by a 2-fold increase in hepatic fatty-acid biosynthesis.93 Dietary copper deficiency was demonstrated to increase hepatic FAS activity associated with a reduction in gene transcription. FAS gene transcription was suggested to be dependent on the hepatic thiol redox state.93 This mechanism may mediate the effects of dietary copper on FAS activity and gene expression.

1.15 Conclusions and Implications

Despite the reduction in dietary fat consumption through massive promotion of low-fat foods, obesity has not ceased to increase.94 This suggests that carbohydrates may be contributing to fat accumulation in humans. This is, in part, addressed by increased interest in the role of glycemic index in energy metabolism, obesity, and diabetes.

In a typical American diet (relatively high in fat), fatty acids would be derived primarily from lipoprotein triglycerides via the action of the lipopro-tein lipase (LPL). As discussed in this chapter, although lipogenesis in humans has been considered as very limited for a long time, available studies clearly demonstrate that fatty acid biosynthesis is important enough in humans to be studied for its relevance to disorders of lipid metabolism. Limited data are available concerning regulation of genes of fatty acid biosynthesis in humans. Studies of the highly regulated fatty acid synthase gene as a marker in this pathway provide useful information on how lipogenesis may be regulated in humans. Inhibition of this enzyme has been shown to be beneficial for reductions of body weight95 as well as tumorigenesis96 (an aspect that we did not discuss in this chapter).

Thus, studies of this gene and other genes in fatty acid synthesis may bring additional insights into human diseases linked to abnormal fatty acid synthesis (such as cirrhosis, LPL deficiency).


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