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of pages: 7; 4C: 2, 3, 4
Biochimica et Biophysica Acta xxx (2014) xxx–xxx

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Biochimica et Biophysica Acta

journal homepage: www.elsevier.com/locate/bbalip

1 Transcription factor networks regulating hepatic fatty acid metabolism☆

2Q1 Panagiota Karagianni, Iannis Talianidis ⁎

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3 Biomedical Sciences Research Center Alexander Fleming, 16672 Vari, Greece

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4 a r t i c l e i n f o a b s t r a c t

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5 Article history: Tight regulation of lipid levels is critical for cellular and organismal homeostasis, not only in terms of energy uti- 15
6 Received 7 March 2014 lization and storage, but also to prevent potential toxicity. The liver utilizes a set of hepatic transcription factors to 16
Received in revised form 29 April 2014

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7 regulate the expression of genes implicated in all aspects of lipid metabolism including catabolism, transport, and 17
8 Accepted 1 May 2014
synthesis. In this article, we will review the main transcriptional mechanisms regulating the expression of genes 18
9 Available online xxxx
involved in hepatic lipid metabolism. The principal regulatory pathways are composed of simple modules of tran- 19

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10 Keywords:
scription factor crosstalks, which correspond to building blocks of more complex regulatory networks. These 20
11 Transcription factor transcriptional networks contribute to the regulation of proper lipid homeostasis in parallel to posttranslational 21
12 Nuclear receptor mechanisms and end product-mediated modulation of lipid metabolizing enzymes. This article is part of a Special 22
Fatty acid metabolism Issue entitled Linking transcription to physiology in lipodomics.
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24 Regulatory network
D © 2014 Published by Elsevier B.V.
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1. Introduction apolipoproteins into nascent chylomicrons. These will subsequently

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29 39
pass into the lymphatic circulation, where they will be subject to apoli- 40
30 The major dietary lipids are triacylglycerol, cholesterol, and phos- poprotein exchange, critical for the digestion of their TAG by adipocyte 41
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31 pholipids. Although limited digestion takes place in the mouth and lipase into FAs and glycerol, as well as for the endocytotic uptake of the 42
32 stomach, the majority of lipid break-down starts in the intestine, with chylomicron remnants by the hepatocyte low-density lipoprotein (LDL) 43
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33 the enzymatic function of lipase, cholesterol esterase, and phospholi- receptor, the LDL receptor-related protein (LRP) or scavenger receptor 44
34 pase. Emulsification of triacylglycerol (TAG), aided by bile salts, is re- B1. Chylomicron remnants are processed by lysosomes and their com- 45
quired to render it accessible to pancreatic lipase. Pancreatic lipase ponents are recycled into new very low-density lipoproteins (VLDLs)
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35 46
36 will break down triglycerides into monoglycerides and free fatty acids [1]. Hepatocytes can uptake FAs from the plasma pool via transport pro- 47
37 (FA), which can be absorbed by enterocytes. Within enterocytes, triglyc- teins, like fatty acid transport protein 2 (FATP2), fatty acid transport 48
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38 erides will form again from their components and assemble with protein 5 (FATP5), and the fatty acid translocase CD36 [2–4] (Fig. 1). 49
Another source of lipid in hepatocytes is autophagy, upon which lyso- 50
Abbreviations: ACC, acetyl-CoA carboxylase; ATP, adenosine triphosphate; CAR, consti- somes and lipid droplets are fused into autophagosomes, degradation
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51
tutive androstane receptor; CD36, fatty acid translocase; CEBPα and β, CCAAT/enhancer of which releases FAs, which can enter β oxidation [5]. Finally, FAs can 52
binding proteins alpha and beta; ChREBP, carbohydrate responsive element binding pro-
also be synthesized de novo, from acetyl coenzyme A (CoA) or malonyl 53
tein; CoA, acetyl coenzyme A; COUPTF, chicken ovalbumin upstream promoter transcrip-
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tion factor; CPT1, carnitine palmitoyltransferase 1; Cyp7a1, cholesterol 7a hydroxylase; CoA. Acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) are 54
DGAT, diacylglycerol-acyltransferase; FA, fatty acids; FAS, fatty acid synthase; FATP2, two key enzymes required for this process. 55
fatty acid transport protein 2; FATP5, fatty acid transport protein 5; FXR, farnesoid X recep- Elevated levels of FAs and their metabolites may promote reactive 56
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tor; Hes1, hairy and enhancer of split 1; Hes6, hairy and enhancer of split 6; HNF1α, hepa- oxygen species (ROS) formation and can cause lipotoxicity. To prevent 57
tocyte nuclear factor 1 alpha; HNF4α, hepatocyte nuclear factor 4 alpha; HNF4-LivKO,
liver-specific HNF4α knock-out; LDL, low density lipoprotein; LRH-1, liver receptor homo-
this, FAs are stored as TAGs (three FAs esterified to a glycerol backbone), 58
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log 1; LRP, LDL receptor-related protein; LXR, liver X-activated receptor; mtGPAT, mito- which are relatively inert. Two key enzymes in TAG synthesis are the 59
chondrial glycerol-3-phosphate-acyltransferase; PGC1α, PPARγ coactivator 1 alpha; mitochondrial glycerol-3-phosphate-acyltransferase (mtGPAT) and 60
PPARα, peroxisome proliferator activated receptor alpha; PPARγ, peroxisome proliferator the diacylglycerol-acyltransferase (DGAT) [6]. Conjugation of TAGs to 61
activated receptor gamma; PUFA, polyunsaturated fatty acid; PXR, pregnane X receptor;
the apolipoprotein apoB-100 will allow their packaging to VLDL parti- 62
RAR, retinoic acid receptor; ROS, reactive oxygen species; RXR, retinoid X receptor; SHP,
small heterodimer partner; SREBP, sterol regulatory binding element protein; TAG, triacyl- cles and secretion to the bloodstream. 63
glycerol; TF, transcription factor; TFEB, transcription factor EB; TR, thyroid receptor; VLDL, FA oxidation is a very efficient energy providing process, during 64
very low density lipoprotein which electrons are donated to the electron transport chain to drive 65
☆ This article is part of a Special Issue entitled Linking transcription to physiology in
adenosine triphosphate (ATP) synthesis. Activation of FAs to acyl-CoA 66
lipodomics.
⁎ Corresponding author at: Biomedical Sciences Research Center Alexander Fleming, 34,
by acyl-CoA-synthetase is required for entering the mitochondria, 67
Alexander Fleming Street, 16672 Vari, Athens, Greece. where β-oxidation will take place [7]. Carnitine palmitoyltransferase 1 68
E-mail address: talianidis@fleming.gr (I. Talianidis). (CPT1) is required for the transport of esterified FAs through the 69

http://dx.doi.org/10.1016/j.bbalip.2014.05.001
1388-1981/© 2014 Published by Elsevier B.V.

Please cite this article as: P. Karagianni, I. Talianidis, Transcription factor networks regulating hepatic fatty acid metabolism, Biochim. Biophys.
Acta (2014), http://dx.doi.org/10.1016/j.bbalip.2014.05.001
 2 P. Karagianni, I. Talianidis / Biochimica et Biophysica Acta xxx (2014) xxx–xxx

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Fig. 1. Main fatty acid metabolic pathways in the hepatocyte (uptake, oxidation, VLDL synthesis), including key proteins implicated in these steps.
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70 mitochondrial membrane. Acetyl-CoA can enter the TCA cycle or be con- 2.1. TF interactions: common targets, common partners 100
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71 verted into ketone bodies, when FAs are abundant (Fig. 1).
72 All of these processes are under tight hormonal and nutritional con- Gene regulatory regions are bound by multiple TFs and the tran- 101
73 trol, as the hepatocyte needs to respond to the metabolic state of the scriptional outcome from a specific locus depends on their combinatori- 102
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74 organism. The main hormones involved in the regulation of lipid metab- al function. The interactions of multiple TFs may display additive, 103
75 olism include insulin, glucagon, norepinephrine, glucocorticoids, synergistic, or antagonistic function towards the activation or repres- 104
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76 growth hormone, thyroid hormone, leptin and adiponectin, which acti- sion of the corresponding genes. Some TFs require heterodimerization 105
77 vate specific signaling pathways at different condition. Metabolic en- with another TF in order to bind to a specific promoter. For instance, 106
78 zymes are primarily regulated by their substrates and products or the liver X-activated receptors LXR and LXRβ, activated by sterols and 107
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79 byproducts of the reactions they catalyze. In addition, different post- their oxidized derivatives, oxysterols, that are cholesterol biosynthesis 108
80 translational mechanisms, including regulated complex assemblies intermediates, form heterodimers with retinoic X receptors (RXRs) 109
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81 coupled to membrane translocations, protein modifications like phos- [8]. PPARs also bind to DNA as heterodimers with RXR [9]. PPARα and 110
82 phorylation or acetylation and chaperone-mediated degradation play LXR have been proposed to activate overlapping transcriptional pro- 111
83 important roles in the regulation of enzymatic cascades involved in grams in mouse liver [10]. In some cases, the two factors display antag- 112
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84 lipid homeostasis. onistic activities in the regulation of fatty acid metabolism in the liver. 113
For example, PPAR-induced FA oxidation is suppressed by LXR activa- 114
tion, while LXR-induced lipogenic gene expression is suppressed by
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85 2. Modules of transcriptional control of lipid metabolic genes PPARα [11]. Competition of the two factors for the limited pool of 116
their common obligate heterodimeric partner RXR could contribute to 117
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86 Apart from the post-translational mechanisms, metabolic enzymes their functional antagonism [12]. It is noteworthy that the PPARα-RXR 118
87 are subject to transcriptional control. Interestingly, a small set of hepatic is a permissive heterodimer, as it can also be activated by retinoid 119
88 transcription factors, including hepatocyte nuclear factor 4 alpha binding to the RXR [13]. This provides an example of how regulation 120
89 (HNF4α), CCAAT/enhancer binding proteins alpha and beta (CEBP〈and of a certain target of the heterodimeric PPARα-RXR can depend on 121
90 β), peroxisome proliferator activated receptors alpha and gamma the intracellular ligand availability of both factors. In other cases, 122
91 (PPARα, PPARγ), hairy and enhancer of split 6 (Hes6), sterol regulatory heterodimerization is not obligatory for functional activity, but it can 123
92 binding element proteins (SREBPs), carbohydrate responsive element serve as an alternative to homodimerization. Small heterodimer partner 124
93 binding protein (ChREBP), retinoid X receptor (RXR), retinoic acid re- (SHP) is an atypical orphan nuclear receptor, as it lacks a DNA-binding 125
94 ceptor (RAR), chicken ovalbumin upstream promoter transcription fac- domain [14]. SHP is recruited to promoters through heterodimerization 126
95 tor (COUPTF), farnesoid X receptor (FXR), thyroid receptor (TR), liver X with other nuclear receptors and exerts repressive function on the ac- 127
96 receptor (LXR), appear to be sufficient in their regulated expression tivity of many nuclear receptors, including LXR, liver receptor homolog 128
97 under different physiological conditions. Most of the genes encoding 1 (LRH-1), constitutive androstane receptor (CAR) and pregnane X re- 129
98 hepatic lipid metabolic enzymes are direct transcriptional targets of ceptor (PXR), by inhibiting their interaction with co-activators and lead- 130
99 the above transcription factors. ing to recruitment of co-repressors to their target promoters [15–18]. 131

Please cite this article as: P. Karagianni, I. Talianidis, Transcription factor networks regulating hepatic fatty acid metabolism, Biochim. Biophys.
Acta (2014), http://dx.doi.org/10.1016/j.bbalip.2014.05.001
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132 Many transcription factors (TFs) implicated in lipid metabolism SHP-mediated recruitment of corepressors to its promoter [25]. Similar- 168
133 function as sensors for nutrients or other metabolites. For instance, ly, the constitutive androstane receptor CAR has been proposed to in- 169
134 PPARα is activated by fatty acids and their derivatives and it is known hibit ligand-bound LXR recruitment to the SREBP1c promoter and 170
135 that a phospholipid synthesized by FAS can activate PPARα [19]. Thus, inhibit lipogenesis [26]. SREBP1c inhibits transcriptional activity of 171
136 TFs (including PPARα itself) regulating the expression of FAS, could in- CAR and PXR by physically blocking their interaction with coactivators 172
137 directly modulate PPARα transcriptional activity by influencing the [27]. Consistent with the negative effect on SREBP transcription, CAR 173
138 availability of its agonist. The net transcriptional output will thus and PXR also repress post-translational activation of SREBPs via induc- 174
139 depend on the integration of multiple variables, such as transcription tion of insulin induced gene 1 (Insig-1), which blocks their proteolytic 175
140 factor interplay, sterol, carbohydrate, bile acid or retinoic acid levels activation in the endoplasmic reticulum (ER) [28]. As these two factors 176
141 and other hormonal stimulation, to name a few. mainly function as xenobiotic receptors, their interaction could provide 177
a cross-talk between detoxification pathways and lipid metabolism. 178
142 2.2. Transcriptional regulation of TFs Interestingly, SREBP1c and 2 can also feed-forwardly regulate their 179
own transcription, through SREs present in their promoter/enhancer 180
143 In the case of a simple regulatory event, where one transcription [29,30] (Fig. 3). 181

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144 factor regulates the expression of another transcription factor, the The above examples also illustrate that the cell utilizes multiple 182
145 first factor will indirectly contribute to the activation of the target layers of regulation to tightly control cholesterol and intracellular fatty 183

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146 genes regulated by the second factor. This scheme is greatly extended acid levels. 184
147 when these factors activate more than one downstream TF, generating Another interesting regulatory module arising from the above listed 185
148 transcriptional cascades, which expand the level of complexity [20] examples concerns the regulation of FAS by LXR. LXR regulates the FAS 186

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149 (Fig. 2). gene, both directly through binding to its response element on the pro- 187
150 An illustrative example is SREBP1c, the sterol response element moter [31], as well as indirectly (Fig. 2), by regulating SREBP1c [32] and 188
binding protein. SREBP1c is a nutrient sensing TF, regulating multiple ChREBP expression [33], which are both required for FAS transcription.

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151 189
152 lipogenic genes, including enzymes involved in fatty acid, phospholipid, This gives LXRα a strategic position in the network of nutrient-sensing 190
153 triglyceride, and cholesterol synthesis [21]. SREBP1c has been described TFs, which regulate fatty acid synthesis and triglyceride accumulation 191

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154 as a direct transcriptional target of liver X-activated receptors LXRα and in the liver. ChREBP is a glucose-dependent transcription factor, linking 192
155 LXRβ and their heterodimeric partner RXR [22]. LXRs are activated by a glucose and lipid metabolism. 193
156 variety of sterols, including oxysterols (intermediates of cholesterol D ChREBP directly regulates Klf10, which has been proposed to gener- 194
157 synthesis). The ability of LXRs to activate fatty acid synthesis is largely ate a negative feedback loop repressing the transcriptional activity of 195
158 mediated by SREBP1c. In conditions of excessive sterol levels, LXR- ChREBP [34,35]. The latter is also a direct transcriptional target for 196
159 mediated activation of SREBP1c results in oleate synthesis, which is SREBP1c, HNF4α, TR, while ChREBP transcriptional activity is inhibited 197
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160 the preferred fatty acid for esterification of cholesterol, allowing for its by FXR [36–41]. The latter exerts repressive function on other TFs as 198
161 transport and storage [22]. LXR can also mediate negative regulation well, often through induction of SHP, which functions as a repressor. 199
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162 of SREBP1c under polyunsaturated fatty acid (PUFA) rich diets. PUFAs Such a regulatory interaction has been described between FXR and 200
163 antagonize activation of LXR by its endogenous ligands, leading to tran- HNF4α. FXR induces SHP expression, which in turn co-represses 201
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164 scriptional repression of SREBP1c and reduced fatty acid synthesis [23]. HNF4α [42]. 202
165 PPARα has also been described to regulate SREBP1c expression, Taken together, the above crossregulatory schemes play an impor- 203
166 although this regulation may vary among species [24]. FXR, the bile tant role in the regulation of energy homeostasis, via coordinating 204
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167 acid receptor, has been reported to negatively regulate SREBP1c, via lipid and glucose signaling under different nutritional conditions. 205
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Fig. 2. Examples of cross-regulatory schemes among transcription factors involved in hepatic lipid metabolism. Ovals represent proteins and rectangles genes. Red arrows indicate positive
regulation. Black flat-ended lines represent repression. Grey dashed arrows indicate transcription/translation.

Please cite this article as: P. Karagianni, I. Talianidis, Transcription factor networks regulating hepatic fatty acid metabolism, Biochim. Biophys.
Acta (2014), http://dx.doi.org/10.1016/j.bbalip.2014.05.001
 4 P. Karagianni, I. Talianidis / Biochimica et Biophysica Acta xxx (2014) xxx–xxx

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Fig. 3. Network of key factors regulating Srebp1c transcription, linking cholesterol and lipid metabolism. Red arrows indicate positive regulation. Black flat-ended lines represent
repression.

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206 3. Dynamic regulation of lipid metabolism in response to to a critical role of this factor in the orchestration of hepatic lipid metab- 221

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207 fasting-feeding conditions olism, possibly through regulation of PPARα and PPARγ. Indeed, PPARα 222
mRNA and protein are reduced in HNF4-LivKO mouse, while PPARγ is 223
208 An intricate pattern of cross-regulatory interactions of TFs implicat- increased. PPARα represents a direct transcriptional target of HNF4α.
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209 ed in lipid metabolism was revealed by studies on liver-specific HNF4α Analysis of the effect of HNF4α on the PPARγ gene revealed Hes6 as a 225
210 knock-out (HNF4-LivKO) mice (Fig. 4). HNF4α belongs to the small novel direct transcriptional target of HNF4α [45]. 226
211 group of transcription factors required for establishment and mainte- HNF4α induces expression of Hes6, which is recruited to promoters 227
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212 nance of the hepatic phenotype [43]. It is expressed in the liver from by HNF4α to repress their transcription. Under feeding conditions, Hes6 228
213 early developmental stages throughout the life-time of the organism. mediates repression of a number of promoters, including PPARγ, 229
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214 HNF4α regulates a great number of genes involved in gluconeogenesis, through interaction with HNF4α. The Hes6 promoter is also activated 230
215 bile acid synthesis, conjugation and transport, through direct binding to by the retinoic acid receptor (RAR) in response to its activation by 231
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216 their promoters. The phenotype of HNF4-LivKO mice is characterized by atRA, and repressed by SHP [46]. 232
217 massive lipid accumulation in hepatocytes, reduced serum triglyceride Although molecular studies revealed that PPARα is a canonical tran- 233
218 and cholesterol levels [44,45]. The fatty liver phenotype is also accom- scriptional target of HNF4α, independent of Hes6, several of its target 234
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219 panied by increased ketogenesis, as suggested by increased serum β- genes are subject to repression by the HNF4α/Hes6 complex. Such re- 235
220 hydroxybutyrate levels. The phenotype of the HNF4-LivKO mice points pressive function of HNF4α/Hes6 is observed on the promoters of 236
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Fig. 4. Network of key factors regulating hepatic lipid metabolism under feeding/fasting conditions. Red arrows indicate positive regulation. Black flat-ended lines represent repression.

Please cite this article as: P. Karagianni, I. Talianidis, Transcription factor networks regulating hepatic fatty acid metabolism, Biochim. Biophys.
Acta (2014), http://dx.doi.org/10.1016/j.bbalip.2014.05.001
 P. Karagianni, I. Talianidis / Biochimica et Biophysica Acta xxx (2014) xxx–xxx 5

237 Cd36 (a fatty acid transport protein) and Acot1 (an enzyme catalyzing leads to simultaneous repression of SREBP1c and activation of the FAS 301
238 hydrolysis of long-chain acyl-CoAs to FFA), both representing bona gene, it can be explained if we consider FXR as an energy-sensing TF 302
239 fide PPARα targets. In wild-type animals, and under fed conditions, critical for restoring energy balance. 303
240 these two genes are subject to repression by HNF4α/Hes6. Under Collectively, FXR activation reduces de novo FA synthesis and VLDL 304
241 fasting conditions and in the livers of HNF4α LivKO mice, liganded transport and increases FA oxidation. FXR transcription is regulated by 305
242 PPARα replaces HNF4α and Hes6, leading to their transcriptional acti- hepatocyte nuclear factor 1 alpha (HNF1α). Downregulation of FXR 306
243 vation. Similar effect is observed by PPARγ on the CD36 promoter. The through ER stress-mediated inhibition of HNF1α transcriptional activity 307
244 same functional interplay between HNF4α/Hes6 and PPARα operates has been proposed to partly explain aging-induced hepatosteatosis [59]. 308
245 on the Fgf21 and Hmgcs2 promoters, critical regulators of ketogenesis
246 [45] (Fig. 4).
247 Apart from the opposing functions of HNF4α and PPARα on the pro- 5. Cross-talk between autophagy and lipid metabolism 309
248 moters of the above genes, the two factors can also exert synergistic
249 function on other shared targets. This is the case for Cpt1, the gene In addition to endogenous lipogenesis and uptake from the plasma 310
250 encoding carnitine palmitoyl transferase 1, which catalyzes long-chain pool, hepatic FAs can also be released from lysosomes by autophagy. 311

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251 fatty acid transfer into the mitochondria. Studies using the HNF4- The lysosomal–autophagic pathway is activated by starvation and 312
252 LivKO as well as Hnf4α/PPARα double KO animals under feeding or plays a critical role in both lipid catabolism as well as cellular clearance. 313

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253 fasting conditions indicated that in the fed state, HNF4α is the main ac- In contrast, excessive lipid load inhibits autophagy, pointing to the close 314
254 tivator of CPT1α, while under fasting conditions, both HNF4α and connection between lipid metabolism and the autophagic process. To 315
255 PPARα regulate Cpt1 transcription in a synergistic fashion. Again, the maintain lipid homeostasis, autophagy needs to be tightly controlled 316

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256 effect of HNF4α on the Cpt1 promoter is not modulated by Hes6 [45]. in response to metabolic cues and based on the cellular energy status. 317
257 Hes6 did not appear to modulate the activating function of HNF4α Along this line, the transcription factor EB (TFEB), a master regulator 318
on the promoters of two other genes, involved in lipid secretion. of lysosomal biogenesis and autophagy, mediates coordination of this

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258 319
259 These are the MTTP and ApoB encoding genes, essential for VLDL syn- process with lipid catabolism [60]. During starvation, TFEB is induced 320
260 thesis. Both represent direct HNF4α targets, further establishing in the liver and other tissues, while it can positively regulate its own 321

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261 HNF4α as a key regulator of basically all aspects of lipid metabolism in transcription through a feed-back loop. In addition to its own transcrip- 322
262 hepatocytes [45]. tion, TFEB also regulates a great number of lipid metabolic genes, such 323
263 It is known that HNF4α can bind to its own promoter/enhancer and Das FA oxidation, transport, and lipid biosynthesis products. The broad ef- 324
264 regulate its own expression. Interestingly, Hes6 is recruited to HNF4α fect of TFEB on hepatic lipid metabolism is largely mediated through 325
265 regulatory regions to repress its activation, thus pointing to a negative PPARα and the PPARγ coactivator 1 alpha (PGC1α). Interestingly, this 326
266 feedback mode of regulation [47,48]. regulatory axis appears to be evolutionary conserved, suggesting that 327
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267 Inhibition of PPARγ has also been reported for Hes1, another repres- TFEB-regulated autophagy processes are important for organismal ad- 328
268 sor, which is induced by cAMP signaling and repressed by glucocorticoid aptation to starvation [60]. 329
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269 receptor [49]. Unlike the Hes6 mediated repression of PPARγ, which de-
270 pends on HNF4α recruitment to the PPARγ promoter, repression of
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271 PPARγ by Hes1, does not seem to depend on other TFs. 6. Concluding remarks: TF networks in lipid homeostasis 330
272 The above complex regulatory network, composed of auto-
273 regulatory, feed-forward and feed-back loop modules (Fig. 2) has been The models presented here illustrate the complexity of cross- 331
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274 proposed to provide a bistable system, allowing cells to switch between regulatory interactions between TFs implicated in hepatic lipid metabo- 332
275 the fed and fasted state [45]. lism. In fact, the regulatory schemes described above represent a simpli- 333
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fied version of the interactions, mainly focusing on direct transcriptional, 334

276 4. Role of FXR in the cross-talk between metabolic pathways rather than on the plethora of post-transcriptional and post-translational 335
regulatory events, which greatly increase the magnitude of regulatory
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277 FXR is a bile acid sensor regulating bile acid, lipid, and glucose me- capacity of a given set of factors. 337
278 tabolism. Negative regulation of hepatic glycolysis and lipogenesis is All major homeostatic processes are subject to regulation by multi- 338
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279 largely mediated by its target SHP [50]. Upon activation, FXR induces ex- ple TFs. This could allow integration of multiple input signals to define 339
280 pression of SHP, an atypical orphan nuclear receptor, which lacks a DNA the outcome of a metabolic process under specific conditions of the 340
281 binding domain and functions as a corepressor of multiple NRs, includ- cell. Multiple TF networks also result in cross-talk between different sig- 341
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282 ing LXR. FXR represses SREBP1c and MTTP via SHP mediated inhibition naling pathways. Network organization could also provide means for 342
283 of co-activator recruitment. Similarly, FXR induced SHP represses HNF4 amplification of signaling events, both in terms of response intensity, in- 343
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284 (Fig. 2). FXR can also directly activate PPARα signaling [51]. In a feed- cluding positive feed-back and feed-forward loops, as well as the num- 344
285 back loop, PPARα has been proposed to also activate FXR expression, ber of downstream targets. This latter would generate pyramidal-like 345
286 although there is conflicting evidence on this mechanism [52]. The branching of a small set of activators to increased downstream effectors, 346
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287 role of FXR in lipid metabolism is highlighted by the phenotype of which could in turn function as regulators of other effectors and so on. 347
288 FXR-deficient mice. These mice display elevated serum high-density li- Intrinsic regulation can also be an advantage of networks integrating 348
289 poprotein, cholesterol, and TG levels, and reduced expression of hepatic negative feed-back loops. In this way, networks could also provide a 349
290 scavenger receptor class-B1 (SRB1), which facilitates cholesterol uptake means of timing the response to signals. Interestingly, such interactions 350
291 from the blood [53]. allow for one transcription factor to regulate another transcription fac- 351
292 FXR also regulates other proteins involved in lipid metabolism, such tor in two time scales, both directly and indirectly through an interme- 352
293 as phospholipid transfer protein, apolipoprotein C-II, apolipoprotein E, diate factor. In addition to rapid and strong ON/OFF responses, network 353
294 and paraoxonase [54–58]. In addition to directly regulating lipid meta- organization also allows for fine tuning and quantitative regulation of 354
295 bolic genes, like FAS, FXR also regulates the expression of some of particular pathways, perhaps also supporting greater amplitude of re- 355
296 their key regulators, PPARα and LXR. SHP activation also leads to repres- sponses. Focusing on the metabolic paradigm, networks allow for paral- 356
297 sion of LRH1, which mediates expression of genes such as cholesterol 7a lel processing of intracellular metabolites and other signaling events. 357
298 hydroxylase (Cyp7a1). Downregulation of SREBP1c expression by FXR Finally, network organization allows for greater stability of a particular 358
299 leads to a decreased expression of its target genes, such as malic enzyme state, often also providing compensatory alternative factors. Stability 359
300 [25]. Although it may at first seem contradictory that FXR activation and responsiveness are both essential in homeostasis. 360

Please cite this article as: P. Karagianni, I. Talianidis, Transcription factor networks regulating hepatic fatty acid metabolism, Biochim. Biophys.
Acta (2014), http://dx.doi.org/10.1016/j.bbalip.2014.05.001
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Please cite this article as: P. Karagianni, I. Talianidis, Transcription factor networks regulating hepatic fatty acid metabolism, Biochim. Biophys.
Acta (2014), http://dx.doi.org/10.1016/j.bbalip.2014.05.001