MINIREVIEW SREBPs: physiology and pathophysiology of the SREBP family Hitoshi Shimano Department of Internal Medicine (Endocrinoglogy and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, Japan SREBP-2 and sterol regulation The sterol regulatory element-binding protein (SREBP) family, originally identified as basic helix–loop–helix (bHLH) leucine zipper transcription factors by Gold- stein and Brown, is involved in the regulation of genes participating in cholesterol biosynthesis and low-density lipoprotein receptor synthesis [1,2]. They are now estab- lished as global regulators of lipid synthesis. What makes this bHLH family unique is that SREBPs are syn- thesized and located on the endoplasmic reticulum (ER) membrane in their precursor form. To exert transcrip- tional activities, the active N-terminal region of the bHLH needs to undergo proteolytic cleavage for nuclear translocation. Sterol regulation is mainly attributed to this cleavage activity, depending on cellular cholesterol levels. The SREBP cleavage-activating protein (SCAP) functions as a cholesterol sensor. When the cellular cho- lesterol levels are depleted, SCAP binds to and escorts SREBP in COPII vesicles to the Golgi apparatus, where the site 1 and site 2 proteases cleave the SREBPs [3,4]. Upon restoration of cellular cholesterol, Insig, another key regulator of ER membrane proteins, traps and retains the SREBP–SCAP complex at the ER to inhibit SREBP cleavage in the Golgi, thus downregulating sterol and low-density lipoprotein receptor biosynthesis. Keywords cholesterol; diabetes; dyslipidemia; fatty acids; fatty liver; insulin resistance; lipotoxicity; metabolic syndrome; SREBP; trigylcerides Correspondence H. Shimano, Department of Internal Medicine (Endocrinoglogy and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Japan Fax: +81 29 853 3174 Tel: +81 29 853 3053 E-mail: shimano-tky@umin.ac.jp, hshimano@md.tsukuba.ac.jp (Received 2 August 2008, revised 11 November 2008, accepted 18 November 2008) doi:10.1111/j.1742-4658.2008.06806.x Sterol regulatory element-binding proteins (SREBPs) have been established as physiological regulators of lipid synthesis. The molecular mechanisms by which cellular sterol balance and nutritional states regulate SREBP acti- vities are the current research focus of this field. Meanwhile, it has been shown that overnutrition or disturbed energy balance causes accumulation of tissue lipids, leading to metabolic disorders, often referred to as ‘lipotox- icity’. In this overview, I discuss the pathological aspects of SREBPs, which contribute to lipotoxicity in a wide variety of organs, including hepatic insulin resistance in hepatosteatosis, impaired insulin secretion in pancreatic b-cells, diabetic nephropathy, cardiac arrythmiasis, and obesity. Abbreviations bHLH, basic helix–loop–helix; ER, endoplasmic reticulum; IRS-2, insulin receptor substrate-2; PUFA, polyunsaturated fatty acid; SCAP, sterol regulatory element-binding protein cleavage-activating protein; SREBP, sterol regulatory element-binding protein. 616 FEBS Journal 276 (2009) 616–621 ª 2008 The Author Journal compilation ª 2008 FEBS SREBP-1c and lipogenesis The SREBP family consists of three isoforms: SREBP- 1a, SREBP-1c, and SREBP-2. Each isoform has a different regulatory mechanism [5–8]. In contrast to sterol regulation by SREBP-2 at the cleavage level as described above, SREBP-1c activates transcription of genes involved in fatty acid and triglyceride synthesis, such as the genes encoding acetyl-CoA carboxylase, fatty acid synthase, Elovl-6, and stearoyl-CoA desatur- ase. These genes are regulated by SREBP-1c, depend- ing on the nutritional conditions for triglyceride storage. SREBP-1c is also subject to the SCAP–Insig cleavage regulation system, but it is not strictly under sterol regulation. Under conditions of overnutrition, SREBP-1c expression is elevated, and consequently, the levels of nuclear SREBP-1c protein and lipogenesis are enhanced in the liver and adipose tissues. Intake of energy molecules such as sugars, carbohydrates and saturated fatty acids activates SREBP-1c expression, which is eliminated under conditions of fasting and starvation. SREBP-1c activates insulin-mediated lipo- genesis, whereas starvation signals such as glucagon, protein kinase A and AMP-activated protein kinase inhibit SREBP-1c. Glucose metabolism and lipid metabolism are highly linked, as depicted in Fig. 1. The feedback system by SREBP-2 guarantees appro- priate levels of cellular cholesterol. Meanwhile, excess glucose cumulatively activates SREBP-1c and increases triglyceride storage. This scenario explains the physio- logical transcriptional regulation of energy storage in response to the nutritional status. Under energy abun- dance scenarios, acetyl-CoA is used as a substrate for the synthesis of fatty acids and cholesterol. In contrast, in an energy-depleted state, acetyl-CoA serves as fuel for the tricarboxylic acid cycle and ATP production via fatty acid oxidation. SREBP-1c is an upstream regulator of genes for energy storage, and could precipitate cardiovascular risks. Physiologically, this system is important for surviving starvation. However, in modern society, where obesity is a major health problem, these thrifty genes exacerbate metabolic disturbances such as diabetes, hyperlipidemia, and metabolic syndrome [9]. Chronic activation of SREBP-1c in cases of overnutrition can therefore lead to obesity-related problems. SREBP as the global lipid regulator SREBP-1a is highly expressed in growing cells, and it activates the synthesis of a variety of lipids, such as fatty acids, triglycerides, and phospholipids, as well as cholesterol, presumably for the supply of membrane lipids. It has been reported that SREBP may play a role in proliferation in a wide variety of human cancers [10– 13]. Recent reports also suggest that SREBP-1a could be involved in lipid synthesis during the cell cycle [14]. Regulation of SREBP-1a in the cell cycle is mediated through its phosphorylation and ubiquitin-dependent degradation by the Fbw7 ubiquitin ligase, indicating a new mechanism of SREBP regulation [15–18]. In con- trast, we recently reported that overexpression of SREBP-1a activates cyclin-dependent kinase inhibitors such as p21, p27, and p16, and causes cell cycle arrest Glucose Glc6P 6PG G6PD Feedback Pentose phosphate pathway NADPH Pyruvate Malate ME PK Cholesterol synthesis Squalene Cholesterol HMG-CoA reductase SREBP-2 NADPH Pyruvate Acetyl-CoA Citrate acetyl-CoA Oxaloacetate Oxaloacetate ACL ACC HMG-CoA HMG-CoA synthase Citrate Malonyl-CoA Palmitate Malate Mitochondria FAS ACC SCD Fatty acid synthesis Stearate Elovl6 acyl-CoA Glycerol-3-phosphate 1-acylglycerol-3-phosphate CoA Cytosol GPAT SCD Feedforward SREBP-1 Triglyceride DGAT Fig. 1. Regulation of glucose and lipid metabolism by SREBPs. Acetyl-CoA is produced from glycolysis of glucose, and passed into the tricarboxylic acid cycle or used for fatty acid synthesis or cholesterol synthesis. SREBP-2 regulates cholesterol synthetic genes in a sterol-regulatory feed- back fashion, whereas SREBP-1c controls lipogenic genes depending upon energy states. Glc6P, glucose 6-phosphate; G6PD, glucose-6-phosphate dehydrogenase; PK, pyruvate kinase; ME, malic enzyme; ACL, acetyl-CoA lyase; ACC, acetyl-CoA carboxyl- ase; FAS, fatty acid synthase; SCD, stea- royl-CoA desaturase; GPAT, glycerol phosphate acyltransferase; DGAT, diacyl- glycerol acyltransferase; 6PG, 6-phosphoglu- conate. H. Shimano Physiology and pathophysiology of the SREBP family FEBS Journal 276 (2009) 616–621 ª 2008 The Author Journal compilation ª 2008 FEBS 617 at G 1 [19]. In particular, p21 is a direct target of SREBP [20]. The role of SREBP-1a in the regulation of cell growth and the cell cycle might be biphasic and complex, and needs to be further investigated. SREBP is evolutionarily conserved; however, the key lipid molecules that control SREBP activation dif- fer among species. Cellular cholesterol levels strictly and partially determine SREBP-2 and SREBP-1 cleav- age in mammalian cells for sterol regulation and synthesis of other lipids, respectively. Intriguingly, cleavage of SREBP homolog is regulated by cellular phosphatidylethanolamine, the major phospholipid in Drosophila, whereas hypoxia regulates SREBP activa- tion in fission yeast [21,22]. Despite species-specific roles, SREBP is linked to cell growth, which leads us to speculate that SREBP cleavage in the membrane is the cell’s sensory response to stress that manifests through changes in membrane lipid composition. Dif- ferential regulation of SREBP processing by different lipids among species suggests that SREBP is a monitor and controller of cell membrane composition. Pathophysiological aspects of SREBPs in various organs Accumulation of lipids has been linked to functional disturbances in various tissues and organs, often referred to as lipotoxicity [23]. Fatty liver is associated with hepatic insulin resistance and b-cell lipotoxicity with impaired insulin secretion, both of which trigger diabetes. SREBP-1c controls endogenous fatty acid synthesis [24]. It is conceivable that positive energy imbalance chronically activates SREBP-1c, causing lipotoxicity in various tissues and organs. It has been reported that SREBP-1c is involved in hepatosteatosis and pancreatic b-cell dysfunction [25,26]. Insulin resistance in liver and impaired insulin secretion in b-cells Molecular dissection of the underlying mechanisms of lipotoxicity due to cellular stresses such as reactive oxygen species and ER stress caused by lipid peroxida- tion has been conducted [27]. Meanwhile, we have been focusing on the molecular mechanisms by which SREBPs are involved in lipotoxicity. SREBPs directly repress the transcription of insulin receptor substrate-2 (IRS-2), the main insulin signaling molecule in the liver and pancreatic b-cells [8,26]. Suppression of IRS-2 by SREBP-1c in the liver inhibits processes regulating insulin signaling, such as glycogen synthesis, and con- tributes to the physiological switching from glycogen synthesis to fatty acid synthesis during energy reple- tion. Chronic activation of hepatic SREBP-1c causes fatty liver, hypertriglyceridemia, and insulin resistance, leading to the development of metabolic syndrome. SREBP-1c activation causes b-cell dysfunction, leading to impaired insulin secretion [28]. IRS-2 is a key mole- cule for pancreatic b-cell mass, through influencing cell survival or possibly proliferation. Diminished b-cell mass is crucial in the development of diabetes. SREBP-1c inhibition of IRS-2 affects b-cell mass and promotes diabetes. Besides affecting b-cell mass, the other factors by which SREBP-1c could contribute to diabetes include exocytosis of insulin-containing gran- ules by uncoupling protein-2 through ATP consump- tion, and granuphilin through inhibition of the vesicle fusion machinery [29–31]. Fatty acids as modulators of SREBP-1c The protective role of fish oil rich in polyunsaturated fatty acids (PUFAs) against cardiovascular diseases has been long known. In addition to antiplatelet and coagu- lant actions, PUFAs also inhibit lipogenesis and lower tissue and plasma triglyceride levels through inhibition of SREBP-1c. The molecular mechanisms by which PUFAs inhibit SREBP-1c are multiple and complex, and still under investigation. Most importantly, PUFAs inhibit SREBP-1c cleavage for nuclear translocation [32,33], which highlights different regulators of the SREBP cleavage system, SREBP-1c for lipogenesis and SREBP-2 for cholesterol synthesis, although the precise molecular basis is still under investigation. PUFAs also suppress SREBP-1c expression [33–37]. They amelio- rated insulin resistance along with hepatosteatosis in an obese mouse model [38]. In pancreatic b-cells, palmitate impairs and eicosapentaenoic acid restores insulin secretion, and studies conducted on SREBP-1c-deficient islets found that these effects are mediated through regulation of SREBP-1c (Fig. 2) [39]. Chronic kidney diseases and SREBP-1c SREBP-1c is also implicated in chronic kidney dis- eases. Glomerular SREBP-1c has been suggested to be involved in diabetic nephropathy and hyperlipidemia- associated glomerulopathy through activation of reactive oxygen species, NADPH oxidase and, thus, transforming growth factor-b [40–43]. Adipogenesis and SREBP-1c SREBP-1c is also known as ADD1, which has been cloned as a regulator of adipogenesis [44]. The roles of SREBP-1c in adipogenesis are currently controversial. Physiology and pathophysiology of the SREBP family H. Shimano 618 FEBS Journal 276 (2009) 616–621 ª 2008 The Author Journal compilation ª 2008 FEBS In 3T3L1 adipocytes, overexpression of ADD1 ⁄ SREBP-1c slightly enhances triglyceride accumulation. However, chronic activation of SREBP-1c in adipose tissues of transgenic mice with disrupted adipogenesis caused lipodystrophy phenotypes [45], suggesting that inappropriate activation of SREBP-1c impairs normal adipogenesis. However, neither adipogenesis nor lipo- genesis was affected in SREBP-1 knockout mice [46], indicating that its chronic absence could be compen- sated for by other factors, potentially SREBP-2. SREBP-1c expression was unexpectedly suppressed in hypertrophic adipose tissues of ob ⁄ ob mice [47]. These data hamper a consistent evaluation of the role of SREBP-1c in adipogenesis. Although it is likely that SREBP-1c ⁄ ADD1 contributes to adipogenesis and lipogenesis in normal adipocytes, the timing and levels of SREBP-1c action are important for effects on adi- pocyte functions. The gene encoding the cyclin-depen- dent kinase inhibitor p21 is a target gene of SREBP [20]. This finding suggests that the regulation of lipid synthesis is linked to the regulation of cell growth. Recently, we observed that in adipocytes, p21 is involved in adipogenesis and obesity associated with insulin resistance [48]. The exact roles of SREBP-1c ⁄ ADD1 are not yet fully defined. SREBP and parasympathetic function in heart Parasympathetic stimulation of the heart involves activation of GIRK1 ⁄ 4, a G-protein-coupled inward- rectifying potassium channel, and results in an acetylcholine-sensitive atrial potassium current. GIRK1 is a newly identified SREBP target [49]. The regulation of the cardiac parasympathetic response and development of ventricular arrhythmia, especially after myocardial infarction, could be regulated by myocardial SREBP-1c, indicating a relationship between lipid metabolism and the parasympathetic response that may play a role in arrhythmogenesis. Regulation of sulfonylurea channels and other potas- sium channels by SREBPs was also observed in our preliminary evaluation of SREBP-1c-overexpressing b-cells, partially contributing to impaired insulin secre- tion. These data imply that changes in lipid meta- bolism could regulate the physiology of biomembranes potentially through SREBPs, although it is yet to be determined whether other ion channels are direct targets of SREBP. New aspects of SREBP functions To summarize, SREBP-1c is a physiological regulator of lipogenesis, and activation of SREBP could contribute to obesity-related pathophysiology through modification of tissue-specific gene expression as shown in Fig. 3. References 1 Brown MS & Goldstein JL (1997) The SREBP path- way: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89, 331–340. 2 Brown MS & Goldstein JL (1999) A proteolytic path- way that controls the cholesterol content of membranes, cells, and blood. Proc Natl Acad Sci USA 96, 11041– 11048. 3 Brown AJ, Sun L, Feramisco JD, Brown MS & Goldstein JL (2002) Cholesterol addition to ER membranes alters Disturbed energy balance Abnormal activation of SREBP-1c PDX1 IRS-2 p21 Granuphilin Cell cycle arrest Anti-apoptosis Obesity Diabetic nephropathy NA DP H oxidase GIRK Parasympathetic response cardiac arrt y thmo g enesis Insulin resistance Loss of β-cell mass Impaired insulin secretion Fig. 3. Chronic activation of SREBP-1c and pathophysiology in various tissues Indicated are genes responsible for pathological mechanisms for lipotoxicity in various tissues. Granuphilin, p21 and G-protein-activated inwardly rectifying potassium (GIRK) chan- nels are direct SREBP targets [49]. IRS-2 is directly repressed by SREBP [8]. Saturated FA Poly unsaturated FA Activation of SREBP-1c Endogenous fatty acid synthesis Lipotoxicity Liver Pancreatic β cells Insulin resistance Impaired insulin secretion Fig. 2. Regulation of SREBP-1c by saturated fatty acids and PU- FAs. Saturated fatty acids activate, and PUFAs suppress, SREBP- 1c, leading to and protecting from hepatic insulin resistance and pancreatic b-cell insulin secretion, respectively [39]. FA, fatty acid. H. Shimano Physiology and pathophysiology of the SREBP family FEBS Journal 276 (2009) 616–621 ª 2008 The Author Journal compilation ª 2008 FEBS 619 conformation of SCAP, the SREBP escort protein that regulates cholesterol metabolism. Mol Cell 10, 237–245. 4 Espenshade PJ, Li WP & Yabe D (2002) Sterols block binding of COPII proteins to SCAP, thereby controlling SCAP sorting in ER. Proc Natl Acad Sci USA 99, 11694–11699. 5 Horton JD & Shimomura I (1999) Sterol regulatory ele- ment-binding proteins: activators of cholesterol and fatty acid biosynthesis. Curr Opin Lipidol 10, 143–150. 6 Shimano H (2001) Sterol regulatory element-binding proteins (SREBPs): transcriptional regulators of lipid synthetic genes. Prog Lipid Res 40, 439–452. 7 Shimano H (2002) Sterol regulatory element-binding protein family as global regulators of lipid synthetic genes in energy metabolism. Vitam Horm 65, 167–194. 8 Ide T, Shimano H, Yahagi N, Matsuzaka T, Nakakuki M, Yamamoto T, Nakagawa Y, Takahashi A, Suzuki H, Sone H et al. (2004) SREBPs suppress IRS-2-medi- ated insulin signalling in the liver. Nat Cell Biol 6, 351–357. 9 Shimano H (2007) SREBP-1c and TFE3, energy tran- scription factors that regulate hepatic insulin signaling. J Mol Med 85, 437–444. 10 Swinnen JV, Heemers H, Deboel L, Foufelle F, Heyns W & Verhoeven G (2000) Stimulation of tumor-associ- ated fatty acid synthase expression by growth factor activation of the sterol regulatory element-binding protein pathway. Oncogene 19, 5173–5181. 11 Li JN, Mahmoud MA, Han WF, Ripple M & Pizer ES (2000) Sterol regulatory element-binding protein-1 par- ticipates in the regulation of fatty acid synthase expres- sion in colorectal neoplasia. Exp Cell Res 261, 159–165. 12 Heemers H, Maes B, Foufelle F, Heyns W, Verhoeven G & Swinnen JV (2001) Androgens stimulate lipogenic gene expression in prostate cancer cells by activation of the sterol regulatory element-binding protein cleavage activating protein ⁄ sterol regulatory element-binding protein pathway. Mol Endocrinol 15, 1817–1828. 13 Yang YA, Morin PJ, Han WF, Chen T, Bornman DM, Gabrielson EW & Pizer ES (2003) Regulation of fatty acid synthase expression in breast cancer by sterol regu- latory element binding protein-1c. Exp Cell Res 282, 132–137. 14 Sundqvist A & Ericsson J (2003) Transcription-depen- dent degradation controls the stability of the SREBP family of transcription factors. Proc Natl Acad Sci USA 100, 13833–13838. 15 Bengoechea-Alonso MT & Ericsson J (2006) Cdk1 ⁄ - cyclin B-mediated phosphorylation stabilizes SREBP1 during mitosis. Cell Cycle 5, 1708–1718. 16 Punga T, Bengoechea-Alonso MT & Ericsson J (2006) Phosphorylation and ubiquitination of the transcription factor sterol regulatory element-binding protein-1 in response to DNA binding. J Biol Chem 281, 25278– 25286. 17 Bengoechea-Alonso MT, Punga T & Ericsson J (2005) Hyperphosphorylation regulates the activity of SREBP1 during mitosis. Proc Natl Acad Sci USA 102, 11681– 11686. 18 Sundqvist A, Bengoechea-Alonso MT, Ye X, Lukiyan- chuk V, Jin J, Harper JW & Ericsson J (2005) Control of lipid metabolism by phosphorylation-dependent deg- radation of the SREBP family of transcription factors by SCF(Fbw7). Cell Metab 1, 379–391. 19 Nakakuki M, Shimano H, Inoue N, Tamura M, Matsu- zaka T, Nakagawa Y, Yahagi N, Toyoshima H, Sato R & Yamada N (2007) A transcription factor of lipid synthesis, sterol regulatory element-binding protein (SREBP)-1a causes G(1) cell-cycle arrest after accumu- lation of cyclin-dependent kinase (cdk) inhibitors. FEBS J 274, 4440–4452. 20 Inoue N, Shimano H, Nakakuki M, Matsuzaka T, Nakagawa Y, Yamamoto T, Sato R, Takahashi A, Sone H, Yahagi N et al. (2005) Lipid synthetic tran- scription factor SREBP-1a activates p21WAF1 ⁄ CIP1, a universal cyclin-dependent kinase inhibitor. Mol Cell Biol 25, 8938–8947. 21 Rawson RB (2003) The SREBP pathway – insights from Insigs and insects. Nat Rev Mol Cell Biol 4, 631– 640. 22 Hughes AL, Todd BL & Espenshade PJ (2005) SREBP pathway responds to sterols and functions as an oxygen sensor in fission yeast. Cell 120, 831–842. 23 Unger RH (1995) Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical impli- cations. Diabetes 44, 863–870. 24 Shimano H, Yahagi N, Amemiya-Kudo M, Hasty AH, Osuga J, Tamura Y, Shionoiri F, Iizuka Y, Ohashi K, Harada K et al. (1999) Sterol regulatory element-bind- ing protein-1 as a key transcription factor for nutri- tional induction of lipogenic enzyme genes. J Biol Chem 274, 35832–35839. 25 Yahagi N, Shimano H, Hasty AH, Matsuzaka T, Ide T, Yoshikawa T, Amemiya-Kudo M, Tomita S, Oka- zaki H, Tamura Y et al. (2002) Absence of sterol regu- latory element-binding protein-1 (SREBP-1) ameliorates fatty livers but not obesity or insulin resistance in Lep(ob) ⁄ Lep(ob) mice. J Biol Chem 277, 19353–19357. 26 Takahashi A, Motomura K, Kato T, Yoshikawa T, Nakagawa Y, Yahagi N, Sone H, Suzuki H, Toyoshima H, Yamada N et al. (2005) Transgenic mice overex- pressing nuclear SREBP-1c in pancreatic beta-cells. Diabetes 54, 492–499. 27 Unger RH (2003) Minireview: weapons of lean body mass destruction: the role of ectopic lipids in the meta- bolic syndrome. Endocrinology 144, 5159–5165. 28 Shimano H, Amemiya-Kudo M, Takahashi A, Kato T, Ishikawa M & Yamada N (2007) Sterol regulatory ele- ment-binding protein-1c and pancreatic beta-cell dys- function. Diabetes Obes Metab 9(Suppl. 2), 133–139. Physiology and pathophysiology of the SREBP family H. Shimano 620 FEBS Journal 276 (2009) 616–621 ª 2008 The Author Journal compilation ª 2008 FEBS 29 Zhang CY, Baffy G, Perret P, Krauss S, Peroni O, Grujic D, Hagen T, Vidal-Puig AJ, Boss O, Kim YB et al. (2001) Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes. Cell 105, 745–755. 30 Yamashita T, Eto K, Okazaki Y, Yamashita S, Yamau- chi T, Sekine N, Nagai R, Noda M & Kadowaki T (2004) Role of uncoupling protein-2 up-regulation and triglyceride accumulation in impaired glucose-stimulated insulin secretion in a beta-cell lipotoxicity model overex- pressing sterol regulatory element-binding protein-1c. Endocrinology 145, 3566–3577. 31 Kato T, Shimano H, Yamamoto T, Yokoo T, Endo Y, Ishikawa M, Matsuzaka T, Nakagawa Y, Kumadaki S, Yahagi N et al. (2006) Granuphilin is activated by SREBP-1c and involved in impaired insulin secretion in diabetic mice. Cell Metab 4, 143–154. 32 Hannah VC, Ou J, Luong A, Goldstein JL & Brown MS (2001) Unsaturated fatty acids down-regulate srebp isoforms 1a and 1c by two mechanisms in HEK-293 cells. J Biol Chem 276, 4365–4372. 33 Yahagi N, Shimano H, Hasty AH, Amemiya-Kudo M, Okazaki H, Tamura Y, Iizuka Y, Shionoiri F, Ohashi K, Osuga J et al. (1999) A crucial role of sterol regula- tory element-binding protein-1 in the regulation of lipogenic gene expression by polyunsaturated fatty acids. J Biol Chem 274, 35840–35844. 34 Kim HJ, Takahashi M & Ezaki O (1999) Fish oil feed- ing decreases mature sterol regulatory element-binding protein 1 (SREBP-1) by down-regulation of SREBP-1c mRNA in mouse liver. A possible mechanism for down-regulation of lipogenic enzyme mRNAs. J Biol Chem 274, 25892–25898. 35 Xu J, Nakamura MT, Cho HP & Clarke SD (1999) Sterol regulatory element binding protein-1 expression is sup- pressed by dietary polyunsaturated fatty acids. A mecha- nism for the coordinate suppression of lipogenic genes by polyunsaturated fats. J Biol Chem 274, 23577–23583. 36 Nakatani T, Kim HJ, Kaburagi Y, Yasuda K & Ezaki O (2003) A low fish oil inhibits SREBP-1 proteolytic cascade, while a high-fish-oil feeding decreases SREBP- 1 mRNA in mice liver: relationship to anti-obesity. J Lipid Res 44, 369–379. 37 Yoshikawa T, Shimano H, Yahagi N, Ide T, Amemiya- Kudo M, Matsuzaka T, Nakakuki M, Tomita S, Oka- zaki H, Tamura Y et al. (2002) Polyunsaturated fatty acids suppress sterol regulatory element-binding pro- tein 1c promoter activity by inhibition of liver X recep- tor (LXR) binding to LXR response elements. J Biol Chem 277, 1705–1711. 38 Sekiya M, Yahagi N, Matsuzaka T, Najima Y, Nak- akuki M, Nagai R, Ishibashi S, Osuga J, Yamada N & Shimano H (2003) Polyunsaturated fatty acids amelio- rate hepatic steatosis in obese mice by SREBP-1 suppression. Hepatology 38, 1529–1539. 39 Kato T, Shimano H, Yamamoto T, Ishikawa M, Kumadaki S, Matsuzaka T, Nakagawa Y, Yahagi N, Nakakuki M, Hasty AH et al. (2008) Palmitate impairs and eicosapentaenoate restores insulin secretion through regulation of SREBP-1c in pancreatic islets. Diabetes 57, 2382–2392. 40 Sun L, Halaihel N, Zhang W, Rogers T & Levi M (2002) Role of sterol regulatory element-binding pro- tein 1 in regulation of renal lipid metabolism and glom- erulosclerosis in diabetes mellitus. J Biol Chem 277, 18919–18927. 41 Jiang T, Liebman SE, Lucia MS, Li J & Levi M (2005) Role of altered renal lipid metabolism and the sterol regulatory element binding proteins in the pathogenesis of age-related renal disease. Kidney Int 68, 2608–2620. 42 Wang Z, Jiang T, Li J, Proctor G, McManaman JL, Lucia S, Chua S & Levi M (2005) Regulation of renal lipid metabolism, lipid accumulation, and glomerulo- sclerosis in FVBdb ⁄ db mice with type 2 diabetes. Diabe- tes 54, 2328–2335. 43 Ishigaki N, Yamamoto T, Shimizu Y, Kobayashi K, Yatoh S, Sone H, Takahashi A, Suzuki H, Yamagata K, Yamada N et al. (2007) Involvement of glomerular SREBP-1c in diabetic nephropathy. Biochem Biophys Res Commun 364, 502–508. 44 Kim JB & Spiegelman BM (1996) ADD1 ⁄ SREBP1 pro- motes adipocyte differentiation and gene expression linked to fatty acid metabolism. Genes Dev 10, 1096– 1107. 45 Shimomura I, Hammer RE, Richardson JA, Ikemoto S, Bashmakov Y, Goldstein JL & Brown MS (1998) Insu- lin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev 12, 3182–3194. 46 Shimano H, Shimomura I, Hammer RE, Herz J, Goldstein JL, Brown MS & Horton JD (1997) Elevated levels of SREBP-2 and cholesterol synthesis in livers of mice homozygous for a targeted disruption of the SREBP-1 gene. J Clin Invest 100, 2115–2124. 47 Soukas A, Cohen P, Socci ND & Friedman JM (2000) Leptin-specific patterns of gene expression in white adipose tissue. Genes Dev 14, 963–980. 48 Inoue N, Yahagi N, Yamamoto T, Ishikawa M, Watanabe K, Matsuzaka T, Nakagawa Y, Takeuchi Y, Kobayashi K, Takahashi A et al. (2008) Cyclin-depen- dent kinase inhibitor, p21WAF1 ⁄ CIP1, is involved in adipocyte differentiation and hypertrophy, linking to obesity, and insulin resistance. J Biol Chem 283, 21220–21229. 49 Park HJ, Georgescu SP, Du C, Madias C, Aronovitz MJ, Welzig CM, Wang B, Begley U, Zhang Y, Blau- stein RO et al. (2008) Parasympathetic response in chick myocytes and mouse heart is controlled by SREBP. J Clin Invest 118, 259–271. H. Shimano Physiology and pathophysiology of the SREBP family FEBS Journal 276 (2009) 616–621 ª 2008 The Author Journal compilation ª 2008 FEBS 621 . MINIREVIEW SREBPs: physiology and pathophysiology of the SREBP family Hitoshi Shimano Department of Internal Medicine (Endocrinoglogy and Metabolism),. target of SREBP [20]. The role of SREBP- 1a in the regulation of cell growth and the cell cycle might be biphasic and complex, and needs to be further investigated. SREBP