The tetraspanin transmembrane protein CD53 mediates dyslipidemia and integrates inflammatory and metabolic signaling in hepatocytes
2022; Elsevier BV; Volume: 299; Issue: 2 Linguagem: Inglês
10.1016/j.jbc.2022.102835
ISSN1083-351X
AutoresCassandra B. Higgins, Joshua A. Adams, Matthew H. Ward, Zev J. Greenberg, Małgorzata Milewska, Jiameng Sun, Yiming Zhang, Luana Chiquetto Paracatu, Dong Qian, Samuel Ballentine, Weikai Li, Ilona Wandzik, Laura G. Schuettpelz, Brian J. DeBosch,
Tópico(s)Cell Adhesion Molecules Research
ResumoTetraspanins are transmembrane signaling and proinflammatory proteins. Prior work demonstrates that the tetraspanin, CD53/TSPAN25/MOX44, mediates B-cell development and lymphocyte migration to lymph nodes and is implicated in various inflammatory diseases. However, CD53 is also expressed in highly metabolic tissues, including adipose and liver; yet its function outside the lymphoid compartment is not defined. Here, we show that CD53 demarcates the nutritional and inflammatory status of hepatocytes. High-fat exposure and inflammatory stimuli induced CD53 in vivo in liver and isolated primary hepatocytes. In contrast, restricting hepatocyte glucose flux through hepatocyte glucose transporter 8 deletion or through trehalose treatment blocked CD53 induction in fat- and fructose-exposed contexts. Furthermore, germline CD53 deletion in vivo blocked Western diet–induced dyslipidemia and hepatic inflammatory transcriptomic activation. Surprisingly, metabolic protection in CD53 KO mice was more pronounced in the presence of an inciting inflammatory event. CD53 deletion attenuated tumor necrosis factor alpha–induced and fatty acid + lipopolysaccharide-induced cytokine gene expression and hepatocyte triglyceride accumulation in isolated murine hepatocytes. In vivo, CD53 deletion in nonalcoholic steatohepatitis diet-fed mice blocked peripheral adipose accumulation and adipose inflammation, insulin tolerance, and liver lipid accumulation. We then defined a stabilized and trehalase-resistant trehalose polymer that blocks hepatocyte CD53 expression in basal and over-fed contexts. The data suggest that CD53 integrates inflammatory and metabolic signals in response to hepatocyte nutritional status and that CD53 blockade may provide a means by which to attenuate pathophysiology in diseases that integrate overnutrition and inflammation, such as nonalcoholic steatohepatitis and type 2 diabetes. Tetraspanins are transmembrane signaling and proinflammatory proteins. Prior work demonstrates that the tetraspanin, CD53/TSPAN25/MOX44, mediates B-cell development and lymphocyte migration to lymph nodes and is implicated in various inflammatory diseases. However, CD53 is also expressed in highly metabolic tissues, including adipose and liver; yet its function outside the lymphoid compartment is not defined. Here, we show that CD53 demarcates the nutritional and inflammatory status of hepatocytes. High-fat exposure and inflammatory stimuli induced CD53 in vivo in liver and isolated primary hepatocytes. In contrast, restricting hepatocyte glucose flux through hepatocyte glucose transporter 8 deletion or through trehalose treatment blocked CD53 induction in fat- and fructose-exposed contexts. Furthermore, germline CD53 deletion in vivo blocked Western diet–induced dyslipidemia and hepatic inflammatory transcriptomic activation. Surprisingly, metabolic protection in CD53 KO mice was more pronounced in the presence of an inciting inflammatory event. CD53 deletion attenuated tumor necrosis factor alpha–induced and fatty acid + lipopolysaccharide-induced cytokine gene expression and hepatocyte triglyceride accumulation in isolated murine hepatocytes. In vivo, CD53 deletion in nonalcoholic steatohepatitis diet-fed mice blocked peripheral adipose accumulation and adipose inflammation, insulin tolerance, and liver lipid accumulation. We then defined a stabilized and trehalase-resistant trehalose polymer that blocks hepatocyte CD53 expression in basal and over-fed contexts. The data suggest that CD53 integrates inflammatory and metabolic signals in response to hepatocyte nutritional status and that CD53 blockade may provide a means by which to attenuate pathophysiology in diseases that integrate overnutrition and inflammation, such as nonalcoholic steatohepatitis and type 2 diabetes. The tetraspanins represent an expansive and diverse family of membrane-spanning receptors that mediate multiple processes across several cell types. These proteins have both intracellular and extracellular domains and act in concert as part of microdomains with other membrane surface proteins to regulate adhesion, migration, cellular fusion, proliferation, and signaling (1Kummer D. Steinbacher T. Schwietzer M.F. Thölmann S. Ebnet K. Tetraspanins: integrating cell surface receptors to functional microdomains in homeostasis and disease.Med. Microbiol. Immunol. 2020; 209: 397-405Crossref PubMed Scopus (20) Google Scholar, 2Charrin S. Jouannet S. Boucheix C. Rubinstein E. Tetraspanins at a glance.J. Cell Sci. 2014; 127: 3641-3648Crossref PubMed Scopus (301) Google Scholar, 3Cai S. Deng Y. Peng H. Shen J. Role of tetraspanins in hepatocellular carcinoma.Front. Oncol. 2021; 11723341Crossref Scopus (11) Google Scholar, 4Yeung L. Hickey M.J. 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Tetraspanin CD53: an overlooked regulator of immune cell function.Med. Microbiol. Immunol. 2020; 209: 545-552Crossref PubMed Scopus (29) Google Scholar). Prior data indicate that CD53 mediates B-cell development and for recirculation and homing of both B and T cells to lymph nodes (7Demaria M.C. Yeung L. Peeters R. Wee J.L. Mihaljcic M. Jones E.L. et al.Tetraspanin CD53 promotes lymphocyte recirculation by stabilizing L-selectin surface expression.iScience. 2020; 23101104Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 8Greenberg Z.J. Monlish D.A. Bartnett R.L. Yang Y. Shen G. Li W. et al.The tetraspanin CD53 regulates early B cell development by promoting IL-7R signaling.J. Immunol. 2020; 204: 58Crossref PubMed Scopus (16) Google Scholar). Similarly, CD53 deficiency impaired neutrophil transmigration, thus CD53 likely plays an important role in the adaptive immune response (9Yeung L. Anderson J.M.L. Wee J.L. Demaria M.C. Finsterbusch M. Liu Y.S. et al.Leukocyte tetraspanin CD53 restrains α3 integrin mobilization and facilitates cytoskeletal remodeling and transmigration in mice.J. Immunol. 2020; 205: 521Crossref PubMed Scopus (9) Google Scholar). However, CD53 is expressed across the lymphoid compartment and is thus likely to serve a broader immune function than the current literature suggests. For example, from a disease-specific point of view, CD53 is upregulated in atherosclerotic plaques and during coronary revascularization (10Duran J. Olavarría P.S. Mola M. Götzens V. Carballo J. Pelegrina E.M. et al.Genetic association study of coronary collateral circulation in patients with coronary artery disease using 22 single nucleotide polymorphisms corresponding to 10 genes involved in postischemic neovascularization.BMC Cardiovasc. Disord. 2015; 15: 37Crossref PubMed Scopus (5) Google Scholar, 11Zhao B. Wang D. Liu Y. Zhang X. Wan Z. Wang J. et al.Six-gene signature associated with immune cells in the progression of atherosclerosis discovered by comprehensive bioinformatics analyses.Cardiovasc. Ther. 2020; 20201230513Crossref Scopus (17) Google Scholar, 12Liu C. Zhang H. Chen Y. Wang S. Chen Z. Liu Z. et al.Identifying RBM47, HCK, CD53, TYROBP, and HAVCR2 as hub genes in advanced atherosclerotic plaques by network-based analysis and validation.Front. Genet. 2021; 11602908Crossref Scopus (15) Google Scholar) and is implicated in cancer surveillance and regulation of innate circulating tumor necrosis factor alpha (TNFα) levels in humans (13Bos S.D. Lakenberg N. van der Breggen R. Houwing-Duistermaat J.J. Kloppenburg M. de Craen A.J. et al.A genome-wide linkage scan reveals CD53 as an important regulator of innate TNF-alpha levels.Eur. J. Hum. Genet. 2010; 18: 953-959Crossref PubMed Scopus (22) Google Scholar). Accordingly, CD53 deficiency in humans predisposes to multiple recurrent infections (14Mollinedo F. 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Hepatol. 2020; 17: 81-92Crossref PubMed Scopus (179) Google Scholar). Accordingly, recent transcriptomic studies identified CD53 as a potential immune biomarker for NASH (61Hui S.T. Parks B.W. Org E. Norheim F. Che N. Pan C. et al.The genetic architecture of NAFLD among inbred strains of mice.Elife. 2015; 4: e05607Crossref PubMed Scopus (69) Google Scholar). CD53 expression in adipose tissue correlated to levels of hepatic steatosis, as quantified by hepatic triglyceride (TG) levels in a panel of mouse strains, and is associated with adipose tissue inflammation in previous studies of obesity (61Hui S.T. Parks B.W. Org E. Norheim F. Che N. Pan C. et al.The genetic architecture of NAFLD among inbred strains of mice.Elife. 2015; 4: e05607Crossref PubMed Scopus (69) Google Scholar, 62Nair S. Lee Y.H. Rousseau E. Cam M. Tataranni P.A. 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Rep. 2016; 638586Crossref Scopus (76) Google Scholar, 35DeBosch B.J. Heitmeier M.R. Mayer A.L. Higgins C.B. Crowley J.R. Kraft T.E. et al.Trehalose inhibits solute carrier 2A (SLC2A) proteins to induce autophagy and prevent hepatic steatosis.Sci. Signal. 2016; 9: ra21Crossref PubMed Scopus (200) Google Scholar, 38Mayer A.L. Higgins C.B. Feng E.H. Adenekan O. Zhang Y. DeBosch B.J. et al.Enhanced hepatic PPARα activity links GLUT8 deficiency to augmented peripheral fasting responses in male mice.Endocrinology. 2018; 159: 2110-2126Crossref PubMed Scopus (12) Google Scholar). We further show that CD53 cell-autonomously mediates TNFα and lipopolysaccharide (LPS) proinflammatory signaling in hepatocytes. In vivo, targeted germline CD53 deletion protected against Western diet (WD)–induced hepatic inflammatory gene expression, and NASH diet–induced peripheral fat, hepatic lipid accumulation, and insulin intolerance. We then identify a trehalose polymer, pTreA40, which induces hepatocyte fasting–like signaling via AMPK, FGF21, PGC1α, and Arg2 signaling (31Higgins C.B. Mayer A.L. Zhang Y. Franczyk M. Ballentine S. Yoshino J. et al.SIRT1 selectively exerts the metabolic protective effects of hepatocyte nicotinamide phosphoribosyltransferase.Nat. Commun. 2022; 13: 1074Crossref PubMed Scopus (11) Google Scholar, 35DeBosch B.J. Heitmeier M.R. Mayer A.L. Higgins C.B. Crowley J.R. Kraft T.E. et al.Trehalose inhibits solute carrier 2A (SLC2A) proteins to induce autophagy and prevent hepatic steatosis.Sci. Signal. 2016; 9: ra21Crossref PubMed Scopus (200) Google Scholar, 39Zhang Y H.C. Fortune H.M. Chen P. Stothard A.I. Mayer A.L. Swarts B.M. et al.Hepatocyte arginase 2 is sufficient to convey the therapeutic metabolic effects of fasting.Nat. Commun. 2019; 10: 1587Crossref PubMed Scopus (19) Google Scholar, 44Kading J. Finck B.N. DeBosch B.J. Targeting hepatocyte carbohydrate transport to mimic fasting and calorie restriction.FEBS J. 2021; 288: 3784-3798Crossref PubMed Scopus (7) Google Scholar, 46Zhang Y. Higgins C.B. Van Tine B.A. Bomalaski J.S. DeBosch B.J. Pegylated arginine deiminase drives arginine turnover and systemic autophagy to dictate energy metabolism.Cell Rep. Med. 2022; 3100498Google Scholar, 47Zhang Y. Finck B.N. DeBosch B.J. Driving arginine catabolism to activate systemic autophagy.Autophagy Rep. 2022; 1: 65-69Crossref Google Scholar, 51Zhang Y. DeBosch B.J. Using trehalose to prevent and treat metabolic function: effectiveness and mechanisms.Curr. Opin. Clin. Nutr. Metab. Care. 2019; 22: 303-310Crossref PubMed Scopus (30) Google Scholar) and blocks CD53 expression in hepatocytes. We conclude that CD53 function assumes metabolic and inflammatory functions in hepatocytes under metabolic and proinflammatory duress. We first tested the effect of obesigenic and inflammatory diet (63Farrell G. 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