The gastric epithelium is often exposed to injurious elements and failure of appropriate healing predisposes to ulcers, hemorrhage, and ultimately cancer. We examined the gastric function of CD36, a protein linked to disease and homeostasis. We used the tamoxifen model of gastric injury in mice null for Cd36 (Cd36-/-), with Cd36 deletion in parietal cells (PC-Cd36-/-) or in endothelial cells (EC-Cd36-/-). CD36 expresses on corpus ECs, on PC basolateral membranes, and in gastrin and ghrelin cells. Stomachs of Cd36-/- mice have altered gland organization and secretion, more fibronectin, and inflammation. Tissue respiration and mitochondrial efficiency are reduced. Phospholipids increased and triglycerides decreased. Mucosal repair after injury is impaired in Cd36-/- and EC-Cd36-/-, not in PC-Cd36-/- mice, and is due to defect of progenitor differentiation to PCs, not of progenitor proliferation or mature PC dysfunction. Relevance to humans is explored in the Vanderbilt BioVu using PrediXcan that links genetically-determined gene expression to clinical phenotypes, which associates low CD36 mRNA with gastritis, gastric ulcer, and gastro-intestinal hemorrhage. A CD36 variant predicted to disrupt an enhancer site associates (p < 10-17) to death from gastro-intestinal hemorrhage in the UK Biobank. The findings support role of CD36 in gastric tissue repair, and its deletion associated with chronic diseases that can predispose to malignancy.

Center for Human Nutrition Department of Medicine Washington University School of Medicine St Louis MO USA

Department of Cell Biology and Physiology Washington University School of Medicine St Louis MO USA

Department of Pathology and Immunology Washington University School of Medicine St Louis MO USA

Department of Surgical Oncology Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors 1st Hospital of China Medical University Shenyang China

Departments of Surgery and Cell and Developmental Biology Vanderbilt University Medical Center and VA Medical Center Nashville TN USA

Division of Gastroenterology Department of Medicine Washington University School of Medicine St Louis MO USA

Division of Genetic Medicine Vanderbilt University Medical Center Nashville TN USA

Gastroenterology and Hepatology Section Departments of Medicine and of Molecular and Cellular Biology Baylor College of Medicine Houston TX USA

Institute of Physiology Czech Academy of Sciences Videnska 1083 14220 Prague 4 Czech Republic

Institute of Translational Medicine University of Liverpool Liverpool UK

MRC Epidemiology Unit University of Cambridge Cambridge UK

Zobrazit více v PubMed

Schubert ML. Gastric acid secretion. Curr. Opin. Gastroenterol. 2016;32:452–460I. doi: 10.1097/MOG.0000000000000308. PubMed DOI

Churm R, Davies JS, Stephens JW, Prior SL. Ghrelin function in human obesity and type 2 diabetes: a concise review. Obes. Rev. 2017;18:140–148I. doi: 10.1111/obr.12474. PubMed DOI

Lv, Y., Liang, T., Wang, G. & Li, Z. Ghrelin, a gastrointestinal hormone, regulates energy balance and lipid metabolism. Biosci. Rep. 38, BSR20181061 (2018). PubMed PMC

Virdis A, et al. Human Ghrelin: A Gastric Hormone with Cardiovascular Properties. Curr. Pharm. Des. 2016;22:52–58I. doi: 10.2174/1381612822666151119144458. PubMed DOI

Cammisotto P, Bendayan M. A review on gastric leptin: the exocrine secretion of a gastric hormone. Anat. Cell Biol. 2012;45:1–16I. doi: 10.5115/acb.2012.45.1.1. PubMed DOI PMC

Sobhani I, et al. Vagal stimulation rapidly increases leptin secretion in human stomach. Gastroenterology. 2002;122:259–263I. doi: 10.1053/gast.2002.31385. PubMed DOI

Hardwick JC, Van Den Brink GR, Offerhaus GJ, Van Deventer SJ, Peppelenbosch MP. Leptin is a growth factor for colonic epithelial cells. Gastroenterology. 2001;121:79–90I. doi: 10.1053/gast.2001.25490. PubMed DOI

Meek TH, Morton GJ. The role of leptin in diabetes: metabolic effects. Diabetologia. 2016;59:928–932I. doi: 10.1007/s00125-016-3898-3. PubMed DOI

Yarandi SS, Hebbar G, Sauer CG, Cole CR, Ziegler TR. Diverse roles of leptin in the gastrointestinal tract: modulation of motility, absorption, growth, and inflammation. Nutrition. 2011;27:269–275I. doi: 10.1016/j.nut.2010.07.004. PubMed DOI PMC

Schubert ML, Rehfeld JF. Gastric peptides-gastrin and somatostatin. Compr. Physiol. 2019;10:197–228I. doi: 10.1002/cphy.c180035. PubMed DOI

Green R, et al. Vitamin B(12) deficiency. Nat. Rev. Dis. Prim. 2017;3:17040I. doi: 10.1038/nrdp.2017.40. PubMed DOI

Yeomans ND, Skeljo MV. Repair and healing of established gastric mucosal injury. J. Clin. Gastroenterol. 1991;13(Suppl 1):S37–41I. doi: 10.1097/00004836-199112001-00006. PubMed DOI

Aihara E, et al. Epithelial Regeneration After Gastric Ulceration Causes Prolonged Cell-Type Alterations. Cell. Mol. Gastroenterol. Hepatol. 2016;2:625–647I. doi: 10.1016/j.jcmgh.2016.05.005. PubMed DOI PMC

Meyer AR, Goldenring JR. Injury, repair, inflammation and metaplasia in the stomach. J. Physiol. 2018;596:3861–3867I. doi: 10.1113/JP275512. PubMed DOI PMC

Wong BW, et al. The role of fatty acid beta-oxidation in lymphangiogenesis. Nature. 2017;542:49–54I. doi: 10.1038/nature21028. PubMed DOI

Xiong J, et al. A metabolic basis for endothelial-to-mesenchymal transition. Mol. Cell. 2018;69:689–698. doi: 10.1016/j.molcel.2018.01.010. PubMed DOI PMC

Efeyan A, Comb WC, Sabatini DM. Nutrient-sensing mechanisms and pathways. Nature. 2015;517:302–310I. doi: 10.1038/nature14190. PubMed DOI PMC

Mihaylova MM, et al. Fasting activates fatty acid oxidation to enhance intestinal stem cell function during homeostasis and aging. cell stem cell. 2018;22:769–778. doi: 10.1016/j.stem.2018.04.001. PubMed DOI PMC

Chen L, et al. HNF4 Regulates Fatty Acid Oxidation and Is Required for Renewal of Intestinal Stem Cells in Mice. Gastroenterology. 2020;158:985–999. doi: 10.1053/j.gastro.2019.11.031. PubMed DOI PMC

Chen M, Yang Y, Braunstein E, Georgeson KE, Harmon CM. Gut expression and regulation of FAT/CD36: possible role in fatty acid transport in rat enterocytes. Am. J. Physiol. Endocrinol. Metab. 2001;281:E916–923I. doi: 10.1152/ajpendo.2001.281.5.E916. PubMed DOI

Mills JC, et al. A molecular profile of the mouse gastric parietal cell with and without exposure to Helicobacter pylori. Proc. Natl Acad. Sci. USA. 2001;98:13687–13692I. doi: 10.1073/pnas.231332398. PubMed DOI PMC

Samovski D, et al. Regulation of AMPK activation by CD36 links fatty acid uptake to beta-oxidation. Diabetes. 2015;64:353–359I. doi: 10.2337/db14-0582. PubMed DOI PMC

Canton J, Neculai D, Grinstein S. Scavenger receptors in homeostasis and immunity. Nat. Rev. Immunol. 2013;13:621–634I. doi: 10.1038/nri3515. PubMed DOI

Cifarelli V, et al. CD36 deficiency impairs the small intestinal barrier and induces subclinical inflammation in mice. Cell. Mol. Gastroenterol. Hepatol. 2017;3:82–98I. doi: 10.1016/j.jcmgh.2016.09.001. PubMed DOI PMC

Abumrad NA, Davidson NO. Role of the gut in lipid homeostasis. Physiol. Rev. 2012;92:1061–1085I. doi: 10.1152/physrev.00019.2011. PubMed DOI PMC

Sundaresan S, et al. CD36-dependent signaling mediates fatty acid-induced gut release of secretin and cholecystokinin. Faseb j. 2013;27:1191–1202I. doi: 10.1096/fj.12-217703. PubMed DOI PMC

Tran TT, et al. Luminal lipid regulates CD36 levels and downstream signaling to stimulate chylomicron synthesis. J. Biol. Chem. 2011;286:25201–25210I. doi: 10.1074/jbc.M111.233551. PubMed DOI PMC

Lo HG, et al. A single transcription factor is sufficient to induce and maintain secretory cell architecture. Genes Dev. 2017;31:154–171I. doi: 10.1101/gad.285684.116. PubMed DOI PMC

Capoccia BJ, Huh WJ, Mills JC. How form follows functional genomics: gene expression profiling gastric epithelial cells with a particular discourse on the parietal cell. Physiol. Genomics. 2009;37:67–78I. doi: 10.1152/physiolgenomics.90408.2008. PubMed DOI PMC

Poirier H, Degrace P, Niot I, Bernard A, Besnard P. Localization and regulation of the putative membrane fatty-acid transporter (FAT) in the small intestine. Comparison with fatty acid-binding proteins (FABP) Eur. J. Biochem. 1996;238:368–373I. doi: 10.1111/j.1432-1033.1996.0368z.x. PubMed DOI

Cammisotto PG, Bendayan M. Leptin secretion by white adipose tissue and gastric mucosa. Histol. Histopathol. 2007;22:199–210I. PubMed

Bado A, et al. The stomach is a source of leptin. Nature. 1998;394:790–793I. doi: 10.1038/29547. PubMed DOI

Cinti S, et al. Secretory granules of endocrine and chief cells of human stomach mucosa contain leptin. Int J. Obes. Relat. Metab. Disord. 2000;24:789–793I. doi: 10.1038/sj.ijo.0801228. PubMed DOI

Sobhani I, et al. Leptin secretion and leptin receptor in the human stomach. Gut. 2000;47:178–183I. doi: 10.1136/gut.47.2.178. PubMed DOI PMC

Besnard P. Lipids and obesity: Also a matter of taste? Rev. Endocr. Metab. Disord. 2016;17:159–170I. doi: 10.1007/s11154-016-9355-2. PubMed DOI

Browning KN, Travagli RA. Central nervous system control of gastrointestinal motility and secretion and modulation of gastrointestinal functions. Compr. Physiol. 2014;4:1339–1368I. doi: 10.1002/cphy.c130055. PubMed DOI PMC

Laugerette F, et al. CD36 involvement in orosensory detection of dietary lipids, spontaneous fat preference, and digestive secretions. J. Clin. Investig. 2005;115:3177–3184I. doi: 10.1172/JCI25299. PubMed DOI PMC

Engevik AC, Kaji I, Goldenring JR. The Physiology of the Gastric Parietal Cell. Physiol. Rev. 2020;100:573–602I. doi: 10.1152/physrev.00016.2019. PubMed DOI PMC

Xie G, Drachenberg C, Yamada M, Wess J, Raufman JP. Cholinergic agonist-induced pepsinogen secretion from murine gastric chief cells is mediated by M1 and M3 muscarinic receptors. Am. J. Physiol. Gastrointest. Liver Physiol. 2005;289:G521–529I. doi: 10.1152/ajpgi.00105.2004. PubMed DOI

Takeuchi K, Endoh T, Hayashi S, Aihara T. Activation of Muscarinic Acetylcholine Receptor Subtype 4 Is Essential for Cholinergic Stimulation of Gastric Acid Secretion: Relation to D Cell/Somatostatin. Front Pharm. 2016;7:278I. doi: 10.3389/fphar.2016.00278. PubMed DOI PMC

Huh WJ, et al. Tamoxifen induces rapid, reversible atrophy, and metaplasia in mouse stomach. Gastroenterology. 2012;142:21–24. doi: 10.1053/j.gastro.2011.09.050. PubMed DOI PMC

Saenz JB, Burclaff J, Mills JC. Modeling Murine Gastric Metaplasia Through Tamoxifen-Induced Acute Parietal Cell Loss. Methods Mol. Biol. 2016;1422:329–339I. doi: 10.1007/978-1-4939-3603-8_28. PubMed DOI PMC

Nomura S, et al. Spasmolytic polypeptide expressing metaplasia to preneoplasia in H. felis-infected mice. Gastroenterology. 2004;127:582–594I. doi: 10.1053/j.gastro.2004.05.029. PubMed DOI

Beyaz S, et al. High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature. 2016;531:53–58I. doi: 10.1038/nature17173. PubMed DOI PMC

Knobloch M, et al. A Fatty Acid Oxidation-Dependent Metabolic Shift Regulates Adult Neural Stem Cell Activity. Cell Rep. 2017;20:2144–2155I. doi: 10.1016/j.celrep.2017.08.029. PubMed DOI PMC

Son NH, et al. Endothelial cell CD36 optimizes tissue fatty acid uptake. The. J. Clin. Investig. 2018;128:4329–4342I. doi: 10.1172/JCI99315. PubMed DOI PMC

Miller, M. J., Cusmano-Ozog, K., Oglesbee, D. & Young, S. Laboratory analysis of acylcarnitines, 2020 update: a technical standard of the American College of Medical Genetics and Genomics (ACMG). Genet Med.23, 249–258 (2020). PubMed

Koves TR, et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab. 2008;7:45–56I. doi: 10.1016/j.cmet.2007.10.013. PubMed DOI

Lee HJ, Mayette J, Rapoport SI, Bazinet RP. Selective remodeling of cardiolipin fatty acids in the aged rat heart. Lipids Health Dis. 2006;5:2I. doi: 10.1186/1476-511X-5-2. PubMed DOI PMC

Han X, et al. Alterations in myocardial cardiolipin content and composition occur at the very earliest stages of diabetes: a shotgun lipidomics study. Biochemistry. 2007;46:6417–6428I. doi: 10.1021/bi7004015. PubMed DOI PMC

Nardone G, Laccetti P, Civiletti C, Budillon G. Phospholipid composition of human gastric mucosa: a study of endoscopic biopsy specimens. Gut. 1993;34:456–460I. doi: 10.1136/gut.34.4.456. PubMed DOI PMC

Gamazon ER, et al. Using an atlas of gene regulation across 44 human tissues to inform complex disease- and trait-associated variation. Nat. Genet. 2018;50:956–967I. doi: 10.1038/s41588-018-0154-4. PubMed DOI PMC

Battle A, Brown CD, Engelhardt BE, Montgomery SB. Genetic effects on gene expression across human tissues. Nature. 2017;550:204–213I. doi: 10.1038/nature24277. PubMed DOI PMC

Unlu G, et al. Phenome-based approach identifies RIC1-linked Mendelian syndrome through zebrafish models, biobank associations and clinical studies. Nat. Med. 2020;26:98–109I. doi: 10.1038/s41591-019-0705-y. PubMed DOI PMC

Bycroft C, et al. The UK Biobank resource with deep phenotyping and genomic data. Nature. 2018;562:203–209I. doi: 10.1038/s41586-018-0579-z. PubMed DOI PMC

Kundaje A, et al. Integrative analysis of 111 reference human epigenomes. Nature. 2015;518:317–330I. doi: 10.1038/nature14248. PubMed DOI PMC

Love-Gregory L, et al. Higher chylomicron remnants and LDL particle numbers associate with CD36 SNPs and DNA methylation sites that reduce CD36. J. Lipid Res. 2016;57:2176–2184I. doi: 10.1194/jlr.P065250. PubMed DOI PMC

Allen LH, et al. Biomarkers of Nutrition for Development (BOND): Vitamin B-12 Review. J. Nutr. 2018;148:1995s–2027sI. doi: 10.1093/jn/nxy201. PubMed DOI PMC

Haruma K, et al. Old and New Gut Hormone, Gastrin and Acid Suppressive Therapy. Digestion. 2018;97:340–344I. doi: 10.1159/000485734. PubMed DOI

Dimaline R, Varro A. Novel roles of gastrin. J. Physiol. 2014;592:2951–2958I. doi: 10.1113/jphysiol.2014.272435. PubMed DOI PMC

Hacioglu A, Algin C, Pasaoglu O, Pasaoglu E, Kanbak G. Protective effect of leptin against ischemia-reperfusion injury in the rat small intestine. BMC Gastroenterol. 2005;5:37I. doi: 10.1186/1471-230X-5-37. PubMed DOI PMC

Adeyemi EO, et al. Mechanisms of action of leptin in preventing gastric ulcer. World J. Gastroenterol. 2005;11:4154–4160I. doi: 10.3748/wjg.v11.i27.4154. PubMed DOI PMC

McFarlan JT, et al. In vivo, fatty acid translocase (CD36) critically regulates skeletal muscle fuel selection, exercise performance, and training-induced adaptation of fatty acid oxidation. J. Biol. Chem. 2012;287:23502–23516I. doi: 10.1074/jbc.M111.315358. PubMed DOI PMC

Yoshida Y, et al. Exercise- and training-induced upregulation of skeletal muscle fatty acid oxidation are not solely dependent on mitochondrial machinery and biogenesis. J. Physiol. 2013;591:4415–4426I. doi: 10.1113/jphysiol.2012.238451. PubMed DOI PMC

Nahlé Z, et al. CD36-dependent regulation of muscle FoxO1 and PDK4 in the PPAR delta/beta-mediated adaptation to metabolic stress. J. Biol. Chem. 2008;283:14317–14326I. doi: 10.1074/jbc.M706478200. PubMed DOI PMC

Willet, S. G. et al. Regenerative proliferation of differentiated cells by mTORC1-dependent paligenosis. EMBO J37, e98311 (2018). PubMed PMC

Harayama, T. & Shimizu, T. Roles of polyunsaturated fatty acids, from mediators to membranes. J. Lipid. Res. 61, 1150–1160I (2020). PubMed PMC

Voelker DR, Numata M. Phospholipid regulation of innate immunity and respiratory viral infection. J. Biol. Chem. 2019;294:4282–4289I. doi: 10.1074/jbc.AW118.003229. PubMed DOI PMC

Cui K, et al. Chromatin signatures in multipotent human hematopoietic stem cells indicate the fate of bivalent genes during differentiation. cell stem cell. 2009;4:80–93I. doi: 10.1016/j.stem.2008.11.011. PubMed DOI PMC

Sabari BR, Zhang D, Allis CD, Zhao Y. Metabolic regulation of gene expression through histone acylations. Nat. Rev. Mol. Cell Biol. 2017;18:90–101I. doi: 10.1038/nrm.2016.140. PubMed DOI PMC

Love-Gregory L, et al. Variants in the CD36 gene associate with the metabolic syndrome and high-density lipoprotein cholesterol. Hum. Mol. Genet. 2008;17:1695–1704I. doi: 10.1093/hmg/ddn060. PubMed DOI PMC

Ma X, et al. A common haplotype at the CD36 locus is associated with high free fatty acid levels and increased cardiovascular risk in Caucasians. Hum. Mol. Genet. 2004;13:2197–2205I. doi: 10.1093/hmg/ddh233. PubMed DOI

Peery AF, et al. Burden of gastrointestinal disease in the United States: 2012 update. Gastroenterology. 2012;143:1179–1187. doi: 10.1053/j.gastro.2012.08.002. PubMed DOI PMC

Paluchova V, et al. Lipokine 5-PAHSA Is Regulated by Adipose Triglyceride Lipase and Primes Adipocytes for De Novo Lipogenesis in Mice. Diabetes. 2020;69:300–312I. doi: 10.2337/db19-0494. PubMed DOI PMC

Cajka, T., Smilowitz, J. T. & Fiehn, O. Validating Quantitative Untargeted Lipidomics Across Nine Liquid Chromatography-High-Resolution Mass Spectrometry Platforms. Anal. Chem. 89, 12360-–2368I (2017). PubMed

Ramsey VG, et al. The maturation of mucus-secreting gastric epithelial progenitors into digestive-enzyme secreting zymogenic cells requires Mist1. Development. 2007;134:211–222I. doi: 10.1242/dev.02700. PubMed DOI

Gamazon ER, et al. A gene-based association method for mapping traits using reference transcriptome data. Nat. Genet. 2015;47:1091–1098I. doi: 10.1038/ng.3367. PubMed DOI PMC