†(E Gil-Iturbe is now at Division of Molecular Therapeutics, Department of Psychiatry, Columbia University Irving Medical Center, New York, New York, USA)
Changes in dietary habits have occurred concomitantly with a rise of type 2 diabetes (T2D) and obesity. Intestine is the first organ facing nutrient ingestion and has to adapt its metabolism with these dietary changes. HNF-4γ, a transcription factor member of the nuclear receptor superfamily and mainly expressed in intestine, has been suggested to be involved in susceptibility to T2D. Our aim was to investigate the role of HNF-4γ in metabolic disorders and related mechanisms. Hnf4g−/− mice were fed high-fat/high-fructose (HF-HF) diet for 6 weeks to induce obesity and T2D. Glucose homeostasis, energy homeostasis in metabolic cages, body composition and stool energy composition, as well as gene expression analysis in the jejunum were analyzed. Despite an absence of decrease in calorie intake, of increase in locomotor activity or energy expenditure, Hnf4g−/− mice fed with HF-HF are protected against weight gain after 6 weeks of HF-HF diet. We showed that Hnf4g−/− mice fed HF-HF display an increase in fecal calorie loss, mainly due to intestinal lipid malabsorption. Gene expression of lipid transporters, Fatp4 and Scarb1 and of triglyceride-rich lipoprotein secretion proteins, Mttp and ApoB are decreased in gut epithelium of Hnf4g−/− mice fed HF-HF, showing the HNF-4γ role in intestine lipid absorption. Furthermore, plasma GLP-1 and jejunal GLP-1 content are increased in Hnf4g−/− mice fed HF-HF, which could contribute to the glucose intolerance protection. The loss of HNF-4γ leads to a protection against a diet-induced weight gain and to a deregulated glucose homeostasis, associated with lipid malabsorption.
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Adeli K & Lewis GF 2008 Intestinal lipoprotein overproduction in insulin-resistant states. Current Opinion in Lipidology 19 221–228. (https://doi.org/10.1097/MOL.0b013e3282ffaf82)
Alkaade S & Vareedayah AA 2017 A primer on exocrine pancreatic insufficiency, fat malabsorption, and fatty acid abnormalities. American Journal of Managed Care 23 S203–S209.(https://pubmed.ncbi.nlm.nih.gov/28727474/ )
Archer A, Sauvaget D, Chauffeton V, Bouchet PE, Chambaz J, Pincon-Raymond M, Cardot P, Ribeiro A & Lacasa M 2005 Intestinal apolipoprotein A-IV gene transcription is controlled by two hormone-responsive elements: a role for hepatic nuclear factor-4 isoforms. Molecular Endocrinology 19 2320–2334. (https://doi.org/10.1210/me.2004-0462)
Bansal S, Buring JE, Rifai N, Mora S, Sacks FM & Ridker PM 2007 Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA 298 309–316. (https://doi.org/10.1001/jama.298.3.309)
Baraille F, Ayari S, Carriere V, Osinski C, Garbin K, Blondeau B, Guillemain G, Serradas P, Rousset M & Lacasa M et al.2015 Glucose tolerance is improved in mice invalidated for the nuclear receptor HNF-4gamma: a critical role for enteroendocrine cell lineage. Diabetes 64 2744–2756. (https://doi.org/10.2337/db14-0993)
Battle MA, Konopka G, Parviz F, Gaggl AL, Yang C, Sladek FM & Duncan SA 2006 Hepatocyte nuclear factor 4alpha orchestrates expression of cell adhesion proteins during the epithelial transformation of the developing liver. PNAS 103 8419–8424. (https://doi.org/10.1073/pnas.0600246103)
Beaslas O, Cueille C, Delers F, Chateau D, Chambaz J, Rousset M & Carriere V 2009 Sensing of dietary lipids by enterocytes: a new role for SR-BI/CLA-1. PLoS ONE 4 e4278. (https://doi.org/10.1371/journal.pone.0004278)
Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G, Perlmann T, Renaud JP, Schwabe J & Sladek F et al.2006 International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacological Reviews 58 798–836. (https://doi.org/10.1124/pr.58.4.10)
Berndt SI, Gustafsson S, Magi R, Ganna A, Wheeler E, Feitosa MF, Justice AE, Monda KL, Croteau-Chonka DC & Day FR et al.2013 Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture. Nature Genetics 45 501–512. (https://doi.org/10.1038/ng.2606)
Bookout AL, Jeong Y, Downes M, Yu RT, Evans RM & Mangelsdorf DJ 2006 Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell 126 789–799. (https://doi.org/10.1016/j.cell.2006.06.049)
Bura KS, Lord C, Marshall S, McDaniel A, Thomas G, Warrier M, Zhang J, Davis MA, Sawyer JK & Shah R et al.2013 Intestinal SR-BI does not impact cholesterol absorption or transintestinal cholesterol efflux in mice. Journal of Lipid Research 54 1567–1577. (https://doi.org/10.1194/jlr.M034454)
Cattin AL, Le Beyec J, Barreau F, Saint-Just S, Houllier A, Gonzalez FJ, Robine S, Pincon-Raymond M, Cardot P & Lacasa M et al.2009 Hepatocyte nuclear factor 4alpha, a key factor for homeostasis, cell architecture, and barrier function of the adult intestinal epithelium. Molecular and Cellular Biology 29 6294–6308. (https://doi.org/10.1128/MCB.00939-09)
Charlton M, Krishnan A, Viker K, Sanderson S, Cazanave S, McConico A, Masuoko H & Gores G 2011 Fast food diet mouse: novel small animal model of NASH with ballooning, progressive fibrosis, and high physiological fidelity to the human condition. American Journal of Physiology: Gastrointestinal and Liver Physiology 301 G825–G834. (https://doi.org/10.1152/ajpgi.00145.2011)
Chellappa K, Deol P, Evans JR, Vuong LM, Chen G, Briancon N, Bolotin E, Lytle C, Nair MG & Sladek FM 2016 Opposing roles of nuclear receptor HNF4alpha isoforms in colitis and colitis-associated colon cancer. eLife 5 e10903. (https://doi.org/10.7554/eLife.10903)
Chen L, Toke NH, Luo S, Vasoya RP, Fullem RL, Parthasarathy A, Perekatt AO & Verzi MP 2019 A reinforcing HNF4-SMAD4 feed-forward module stabilizes enterocyte identity. Nature Genetics 51 777–785. (https://doi.org/10.1038/s41588-019-0384-0)
Chen L, Vasoya RP, Toke NH, Parthasarathy A, Luo S, Chiles E, Flores J, Gao N, Bonder EM & Su X et al.2020 HNF4 regulates fatty acid oxidation and is required for renewal of intestinal stem cells in mice. Gastroenterology 158 985 .e9–999.e9. (https://doi.org/10.1053/j.gastro.2019.11.031)
Davidson NO & Shelness GS 2000 Apolipoprotein B: mRNA editing, lipoprotein assembly, and presecretory degradation. Annual Review of Nutrition 20 169–193. (https://doi.org/10.1146/annurev.nutr.20.1.169)
Digel M, Staffer S, Ehehalt F, Stremmel W, Ehehalt R & Fullekrug J 2011 FATP4 contributes as an enzyme to the basal and insulin-mediated fatty acid uptake of C(2)C(1)(2) muscle cells. American Journal of Physiology: Endocrinology and Metabolism 301 E785–E796. (https://doi.org/10.1152/ajpendo.00079.2011)
Dissard R, Klein J, Caubet C, Breuil B, Siwy J, Hoffman J, Sicard L, Ducasse L, Rascalou S & Payre B et al.2013 Long term metabolic syndrome induced by a high fat high fructose diet leads to minimal renal injury in C57BL/6 mice. PLoS ONE 8 e76703. (https://doi.org/10.1371/journal.pone.0076703)
Drewes T, Senkel S, Holewa B & Ryffel GU 1996 Human hepatocyte nuclear factor 4 isoforms are encoded by distinct and differentially expressed genes. Molecular and Cellular Biology 16 925–931. (https://doi.org/10.1128/MCB.16.3.925)
Duez H, Lamarche B, Uffelman KD, Valero R, Cohn JS & Lewis GF 2006 Hyperinsulinemia is associated with increased production rate of intestinal apolipoprotein B-48-containing lipoproteins in humans. Arteriosclerosis, Thrombosis, and Vascular Biology 26 1357–1363. (https://doi.org/10.1161/01.ATV.0000222015.76038.14)
Duez H, Pavlic M & Lewis GF 2008 Mechanism of intestinal lipoprotein overproduction in insulin resistant humans. Atherosclerosis: Supplements 9 33–38. (https://doi.org/10.1016/j.atherosclerosissup.2008.05.013)
Frochot V, Alqub M, Cattin AL, Carriere V, Houllier A, Baraille F, Barbot L, Saint-Just S, Ribeiro A & Lacasa M et al.2012 The transcription factor HNF-4alpha: a key factor of the intestinal uptake of fatty acids in mouse. American Journal of Physiology: Gastrointestinal and Liver Physiology 302 G1253–G1263. (https://doi.org/10.1152/ajpgi.00329.2011)
Gerdin AK, Surve VV, Jonsson M, Bjursell M, Bjorkman M, Edenro A, Schuelke M, Saad A, Bjurstrom S & Lundgren EJ et al.2006 Phenotypic screening of hepatocyte nuclear factor (HNF) 4-gamma receptor knockout mice. Biochemical and Biophysical Research Communications 349 825–832. (https://doi.org/10.1016/j.bbrc.2006.08.103)
Gimeno RE, Hirsch DJ, Punreddy S, Sun Y, Ortegon AM, Wu H, Daniels T, Stricker-Krongrad A, Lodish HF & Stahl A 2003 Targeted deletion of fatty acid transport protein-4 results in early embryonic lethality. Journal of Biological Chemistry 278 49512–49516. (https://doi.org/10.1074/jbc.M309759200)
Haidari M, Leung N, Mahbub F, Uffelman KD, Kohen-Avramoglu R, Lewis GF & Adeli K 2002 Fasting and postprandial overproduction of intestinally derived lipoproteins in an animal model of insulin resistance. Evidence that chronic fructose feeding in the hamster is accompanied by enhanced intestinal de novo lipogenesis and ApoB48-containing lipoprotein overproduction. Journal of Biological Chemistry 277 31646–31655. (https://doi.org/10.1074/jbc.M200544200)
Hayashi AA, Webb J, Choi J, Baker C, Lino M, Trigatti B, Trajcevski KE, Hawke TJ & Adeli K 2011 Intestinal SR-BI is upregulated in insulin-resistant states and is associated with overproduction of intestinal apoB48-containing lipoproteins. American Journal of Physiology: Gastrointestinal and Liver Physiology 301 G326–G337. (https://doi.org/10.1152/ajpgi.00425.2010)
Hsieh J, Hayashi AA, Webb J & Adeli K 2008 Postprandial dyslipidemia in insulin resistance: mechanisms and role of intestinal insulin sensitivity. Atherosclerosis: Supplements 9 7–13. (https://doi.org/10.1016/j.atherosclerosissup.2008.05.011)
Hwang-Verslues WW & Sladek FM 2010 HNF4alpha – role in drug metabolism and potential drug target? Current Opinion in Pharmacology 10 698–705. (https://doi.org/10.1016/j.coph.2010.08.010)
Iqbal J & Hussain MM 2009 Intestinal lipid absorption. American Journal of Physiology: Endocrinology and Metabolism 296 E1183–E1194. (https://doi.org/10.1152/ajpendo.90899.2008)
Layec S, Beyer L, Corcos O, Alves A, Dray X, Amiot A, Stefanescu C, Coffin B, Bretagnol F & Bouhnik Y et al.2013 Increased intestinal absorption by segmental reversal of the small bowel in adult patients with short-bowel syndrome: a case-control study. American Journal of Clinical Nutrition 97 100–108. (https://doi.org/10.3945/ajcn.112.042606)
Levy E, Sinnett D, Thibault L, Nguyen TD, Delvin E & Menard D 1996 Insulin modulation of newly synthesized apolipoproteins B-100 and B-48 in human fetal intestine: gene expression and mRNA editing are not involved. FEBS Letters 393 253–258. (https://doi.org/10.1016/0014-5793(9600896-4)
Lewis GF, Uffelman K, Naples M, Szeto L, Haidari M & Adeli K 2005 Intestinal lipoprotein overproduction, a newly recognized component of insulin resistance, is ameliorated by the insulin sensitizer rosiglitazone: studies in the fructose-fed Syrian golden hamster. Endocrinology 146 247–255. (https://doi.org/10.1210/en.2004-1143)
Li X, Udager AM, Hu C, Qiao XT, Richards N & Gumucio DL 2009 Dynamic patterning at the pylorus: formation of an epithelial intestine-stomach boundary in late fetal life. Developmental Dynamics 238 3205–3217. (https://doi.org/10.1002/dvdy.22134)
Lindeboom RG, van Voorthuijsen L, Oost KC, Rodriguez-Colman MJ, Luna-Velez MV, Furlan C, Baraille F, Jansen PW, Ribeiro A & Burgering BM et al.2018 Integrative multi-omics analysis of intestinal organoid differentiation. Molecular Systems Biology 14 e8227. (https://doi.org/10.15252/msb.20188227)
Milger K, Herrmann T, Becker C, Gotthardt D, Zickwolf J, Ehehalt R, Watkins PA, Stremmel W & Fullekrug J 2006 Cellular uptake of fatty acids driven by the ER-localized acyl-CoA synthetase FATP4. Journal of Cell Science 119 4678–4688. (https://doi.org/10.1242/jcs.03280)
Montenegro-Miranda PS, van der Meer JHM, Jones C, Meisner S, Vermeulen JLM, Koster J, Wildenberg ME, Heijmans J, Boudreau F & Ribeiro A et al.2020 A novel organoid model of damage and repair identifies HNF4alpha as a critical regulator of intestinal epithelial regeneration. Cellular and Molecular Gastroenterology and Hepatology 10 209–223. (https://doi.org/10.1016/j.jcmgh.2020.02.007)
Nogueira JP, Maraninchi M, Beliard S, Padilla N, Duvillard L, Mancini J, Nicolay A, Xiao C, Vialettes B & Lewis GF et al.2012 Absence of acute inhibitory effect of insulin on chylomicron production in type 2 diabetes. Arteriosclerosis, Thrombosis, and Vascular Biology 32 1039–1044. (https://doi.org/10.1161/ATVBAHA.111.242073)
Nordestgaard BG, Benn M, Schnohr P & Tybjaerg-Hansen A 2007 Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA 298 299–308. (https://doi.org/10.1001/jama.298.3.299)
Nordskog BK, Phan CT, Nutting DF & Tso P 2001 An examination of the factors affecting intestinal lymphatic transport of dietary lipids. Advanced Drug Delivery Reviews 50 21–44. (https://doi.org/10.1016/s0169-409x(0100147-8)
Plengvidhya N, Antonellis A, Wogan LT, Poleev A, Borgschulze M, Warram JH, Ryffel GU, Krolewski AS & Doria A 1999 Hepatocyte nuclear factor-4gamma: cDNA sequence, gene organization, and mutation screening in early-onset autosomal-dominant type 2 diabetes. Diabetes 48 2099–2102. (https://doi.org/10.2337/diabetes.48.10.2099)
Ribeiro A, Archer A, Le Beyec J, Cattin A-L, Saint-Just S, Pinçon-Raymond M, Chambaz J, Lacasa M & Cardot P 2007 Hepatic nuclear factor-4, a key transcription factor at the crossroads between architecture and function of epithelia. Recent Patents on Endocrine, Metabolic and Immune Drug Discovery 1 176–181.(https://doi.org/10.2174/187221407780832000)
Robertson MD, Parkes M, Warren BF, Ferguson DJ, Jackson KG, Jewell DP & Frayn KN 2003 Mobilisation of enterocyte fat stores by oral glucose in humans. Gut 52 834–839. (https://doi.org/10.1136/gut.52.6.834)
Saandi T, Baraille F, Derbal-Wolfrom L, Cattin AL, Benahmed F, Martin E, Cardot P, Duclos B, Ribeiro A & Freund JN et al.2013 Regulation of the tumor suppressor homeogene Cdx2 by HNF4alpha in intestinal cancer. Oncogene 32 3782–3788. (https://doi.org/10.1038/onc.2012.401)
Saddar S, Carriere V, Lee WR, Tanigaki K, Yuhanna IS, Parathath S, Morel E, Warrier M, Sawyer JK & Gerard RD et al.2013 Scavenger receptor class B type I is a plasma membrane cholesterol sensor. Circulation Research 112 140–151. (https://doi.org/10.1161/CIRCRESAHA.112.280081)
Sasaki S, Urabe M, Maeda T, Suzuki J, Irie R, Suzuki M, Tomaru Y, Sakaguchi M, Gonzalez FJ & Inoue Y 2018 Induction of hepatic metabolic functions by a novel variant of hepatocyte nuclear factor 4gamma. Molecular and Cellular Biology 38 e00213-18. (https://doi.org/10.1128/MCB.00213-18)
Sauvaget D, Chauffeton V, Citadelle D, Chatelet FP, Cywiner-Golenzer C, Chambaz J, Pincon-Raymond M, Cardot P, Le Beyec J & Ribeiro A 2002 Restriction of apolipoprotein A-IV gene expression to the intestine villus depends on a hormone-responsive element and parallels differential expression of the hepatic nuclear factor 4alpha and gamma isoforms. Journal of Biological Chemistry 277 34540–34548. (https://doi.org/10.1074/jbc.M206074200)
Selvanayagam T, Walker S, Gazzellone MJ, Kellam B, Cytrynbaum C, Stavropoulos DJ, Li P, Birken CS, Hamilton J & Weksberg R et al.2018 Genome-wide copy number variation analysis identifies novel candidate loci associated with pediatric obesity. European Journal of Human Genetics 26 1588–1596. (https://doi.org/10.1038/s41431-018-0189-0)
Shikany JM & White Jr GL 2000 Dietary guidelines for chronic disease prevention. Southern Medical Journal 93 1138–1151 . ( https://pubmed.ncbi.nlm.nih.gov/11142446/ )
Stahel P, Xiao C, Nahmias A & Lewis GF 2020 Role of the gut in diabetic dyslipidemia. Frontiers in Endocrinology 11 116. (https://doi.org/10.3389/fendo.2020.00116)
Stahl A, Hirsch DJ, Gimeno RE, Punreddy S, Ge P, Watson N, Patel S, Kotler M, Raimondi A & Tartaglia LA et al.1999 Identification of the major intestinal fatty acid transport protein. Molecular Cell 4 299–308. (https://doi.org/10.1016/s1097-2765(0080332-9)
Taraviras S, Mantamadiotis T, Dong-Si T, Mincheva A, Lichter P, Drewes T, Ryffel GU, Monaghan AP & Schutz G 2000 Primary structure, chromosomal mapping, expression and transcriptional activity of murine hepatocyte nuclear factor 4gamma. Biochimica et Biophysica Acta 1490 21–32. (https://doi.org/10.1016/s0167-4781(9900232-8)
Torres-Padilla ME, Fougere-Deschatrette C & Weiss MC 2001 Expression of HNF4alpha isoforms in mouse liver development is regulated by sequential promoter usage and constitutive 3′ end splicing. Mechanisms of Development 109 183–193. (https://doi.org/10.1016/s0925-4773(0100521-4)
Tsuchiya H, Ebata Y, Sakabe T, Hama S, Kogure K & Shiota G 2013 High-fat, high-fructose diet induces hepatic iron overload via a hepcidin-independent mechanism prior to the onset of liver steatosis and insulin resistance in mice. Metabolism: Clinical and Experimental 62 62–69. (https://doi.org/10.1016/j.metabol.2012.06.008)
Vine DF, Takechi R, Russell JC & Proctor SD 2007 Impaired postprandial apolipoprotein-B48 metabolism in the obese, insulin-resistant JCR:LA-cp rat: increased atherogenicity for the metabolic syndrome. Atherosclerosis 190 282–290. (https://doi.org/10.1016/j.atherosclerosis.2006.03.013)
Williams KJ 2008 Molecular processes that handle – and mishandle – dietary lipids. Journal of Clinical Investigation 118 3247–3259. (https://doi.org/10.1172/JCI35206)
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