Cell-specific regulation of insulin action and hepatic fibrosis by CEACAM1

Abstract

The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) has reached an epidemic rise worldwide. The disease is a constellation of a broad range of metabolic and histopathologic abnormalities. It begins with hepatic steatosis and progresses to metabolic dysfunction-associated steatohepatitis (MASH), including hepatic fibrosis, apoptosis, and cell injury. Despite ample research effort, the pathogenesis of the disease has not been fully delineated. Whereas insulin resistance is implicated in the early stages of the disease, its role in hepatic fibrosis remains controversial. We have focused our studies on the role of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in hepatocytes and endothelial cells in the metabolic and histopathological dysregulation in MASH. Patients with MASH exhibit lower hepatic CEACAM1 with a progressive decline in hepatocytes and endothelial cells as the fibrosis stage advances. In mice, conditional deletion of CEACAM1 in hepatocytes impairs insulin clearance to cause hyperinsulinemia-driven insulin resistance with steatohepatitis and hepatic fibrosis even when mice are fed a regular chow diet. In contrast, its conditional deletion in endothelial cells causes inflammation-driven hepatic fibrosis without adversely affecting metabolism (mice remain insulin-sensitive and do not develop hepatic steatosis). Thus, this review provides in vivo evidence that supports or discards the role of insulin resistance in liver injury and hepatic fibrosis.

Keywords

Insulin action / insulin resistance / insulin clearance / hepatic steatosis / hepatic fibrosis / liver injury

References

[1] Byrne CD.MASLD, MAFLD, or NAFLD criteria: have we re-created the confusion and acrimony surrounding metabolic syndrome?.Metab Target Organ Damage2024;4:10

[2] Younossi ZM.Non-alcoholic fatty liver disease-a global public health perspective.J Hepatol2019;70:531-44

[3] Wang S.Found in translation-fibrosis in metabolic dysfunction-associated steatohepatitis (MASH).Sci Transl Med2023;15:eadi0759 PMCID:PMC10671253

[4] Goldner D.Nonalcoholic fatty liver disease in children: unique considerations and challenges.Gastroenterology2020;158:1967-83.e1

[5] Díaz LA,Barrera F,Arrese M.The burden of liver disease in Latin America.Ann Hepatol2024;29:101175

[6] Shaheen M,Schrode KM.Reassessment of the hispanic disparity: hepatic steatosis is more prevalent in mexican americans than other hispanics.Hepatol Commun2021;5:2068-79 PMCID:PMC8631095

[7] Shaheen M,Pan D.Sex-specific differences in the association between race/ethnicity and NAFLD among US population.Front Med (Lausanne)2021;8:795421 PMCID:PMC8674562

[8] Driessen S,Anker SD.Metabolic dysfunction-associated steatotic liver disease and the heart.Hepatology2023;Online ahead of print:

[9] Yan L,Wu S,Zhao S.Association between the cardiometabolic index and NAFLD and fibrosis.Sci Rep2024;14:13194 PMCID:PMC11162484

[10] Hirata A,Iida M.Association of nonalcoholic fatty liver disease with arterial stiffness and its metabolomic profiling in japanese community-dwellers.J Atheroscler Thromb2024;31:1031-47 PMCID:PMC11224684

[11] Xu L,Albanis E.Human hepatic stellate cell lines, LX-1 and LX-2: new tools for analysis of hepatic fibrosis.Gut2005;54:142-51 PMCID:PMC1774377

[12] Harrison SA, Bedossa P, Guy CD, et al; MAESTRO-NASH Investigators. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med 2024;390:497-509.

[13] Sevastianova K,Gastaldelli A.Genetic variation in PNPLA3 (adiponutrin) confers sensitivity to weight loss-induced decrease in liver fat in humans.Am J Clin Nutr2011;94:104-11

[14] Wang CW,Shin SJ.The PNPLA3 I148M polymorphism is associated with insulin resistance and nonalcoholic fatty liver disease in a normoglycaemic population.Liver Int2011;31:1326-31

[15] European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO clinical practice guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). Obes Facts 2024;17:374-444. PMCID:PMC11299976

[16] Newsome PN.Incretins (GLP-1 receptor agonists and dual/triple agonists) and the liver.J Hepatol2023;79:1557-65

[17] Puengel T.Pharmacotherapeutic options for metabolic dysfunction-associated steatotic liver disease: where are we today?.Expert Opin Pharmacother2024;25:1249-63

[18] Armstrong MJ,Aithal GP.Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study.Lancet2016;387:679-90

[19] Loomba R, Abdelmalek MF, Armstrong MJ, et al; NN9931-4492 investigators. Semaglutide 2·4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial. Lancet Gastroenterol Hepatol 2023;8:511-22. PMCID:PMC10792518

[20] Speliotes EK, Butler JL, Palmer CD, Voight BF, et al; Hirschhorn JN; GIANT Consortium; MIGen Consortium; NASH CRN. PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease. Hepatology 2010;52:904-12. PMCID:PMC3070300

[21] Sookoian S.Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease.Hepatology2011;53:1883-94

[22] Kantartzis K,Machicao F.Dissociation between fatty liver and insulin resistance in humans carrying a variant of the patatin-like phospholipase 3 gene.Diabetes2009;58:2616-23 PMCID:PMC2768178

[23] Petit JM,Masson D.Specifically PNPLA3-mediated accumulation of liver fat in obese patients with type 2 diabetes.J Clin Endocrinol Metab2010;95:E430-6

[24] Chen LZ,Geng N,Zhang DD.PNPLA3 I148M variant in nonalcoholic fatty liver disease: demographic and ethnic characteristics and the role of the variant in nonalcoholic fatty liver fibrosis.World J Gastroenterol2015;21:794-802 PMCID:PMC4299331

[25] Lee CC,Wagenknecht LE.Insulin clearance and the incidence of type 2 diabetes in Hispanics and African Americans: the IRAS family study.Diabetes Care2013;36:901-7 PMCID:PMC3609510

[26] Shah MH,Looker HC,Krakoff J.Lower insulin clearance is associated with increased risk of type 2 diabetes in native Americans.Diabetologia2021;64:914-22

[27] Matveyenko AV,Gurlo T.Pulsatile portal vein insulin delivery enhances hepatic insulin action and signaling.Diabetes2012;61:2269-79 PMCID:PMC3425431

[28] Lee WH,Kahn CR.Hepatic insulin receptor: new views on the mechanisms of liver disease.Metabolism2023;145:155607 PMCID:PMC10330768

[29] Haeusler RA,Accili D.Biochemical and cellular properties of insulin receptor signalling.Nat Rev Mol Cell Biol2018;19:31-44 PMCID:PMC5894887

[30] Saltiel AR.Insulin signaling in health and disease.J Clin Invest2021;131:142241 PMCID:PMC7773347

[31] Najjar SM,Gastaldelli A.Insulin clearance in health and disease.Annu Rev Physiol2023;85:363-81

[32] Meijer RI.The insulin receptor mediates insulin’s early plasma clearance by liver, muscle, and kidney.Biomedicines2021;9:37 PMCID:PMC7824884

[33] Najjar SM.Hepatic insulin clearance: mechanism and physiology.Physiology (Bethesda)2019;34:198-215 PMCID:PMC6734066

[34] Bergman RN,Ader M.The physiology of insulin clearance.Int J Mol Sci2022;23:1826 PMCID:PMC8836929

[35] Bergman RN,Kabir M,Ader M.Hypothesis: role of reduced hepatic insulin clearance in the pathogenesis of type 2 diabetes.Diabetes2019;68:1709-16 PMCID:PMC6702636

[36] Tokarz VL,Klip A.The cell biology of systemic insulin function.J Cell Biol2018;217:2273-89 PMCID:PMC6028526

[37] Kolka CM.The barrier within: endothelial transport of hormones.Physiology (Bethesda)2012;27:237-47 PMCID:PMC4423824

[38] Najjar SM,Suzuki Y.Insulin-stimulated phosphorylation of recombinant pp120/HA4, an endogenous substrate of the insulin receptor tyrosine kinase.Biochemistry1995;34:9341-9

[39] Najjar SM,Philippe N,Margolis R.pp120/ecto-ATPase, an endogenous substrate of the insulin receptor tyrosine kinase, is expressed as two variably spliced isoforms.J Biol Chem1993;268:1201-6

[40] Sundberg U,Obrink B.The cytoplasmic domain of CEACAM1-L controls its lateral localization and the organization of desmosomes in polarized epithelial cells.J Cell Sci2004;117:1091-104

[41] Formisano P,Gross CN.Receptor-mediated internalization of insulin. Potential role of pp120/HA4, a substrate of the insulin receptor kinase.J Biol Chem1995;270:24073-7

[42] Najjar SM,Fernström MA.Insulin acutely decreases hepatic fatty acid synthase activity.Cell Metab2005;2:43-53

[43] Najjar SM,Ghadieh HE.Regulation of insulin clearance by non-esterified fatty acids.Biomedicines2022;10:1899 PMCID:PMC9405499

[44] Osborne TF.Sterol regulatory element-binding proteins (SREBPs): key regulators of nutritional homeostasis and insulin action.J Biol Chem2000;275:32379-82

[45] Ter Horst KW,Zhang D.Hepatic insulin resistance is not pathway selective in humans with nonalcoholic fatty liver disease.Diabetes Care2021;44:489-98 PMCID:PMC7818337

[46] Zaharia OP, Antoniou S, Bobrov P, et al; GDS Group. Reduced insulin clearance differently relates to increased liver lipid content and worse glycemic control in recent-onset type 2 and type 1 diabetes. Diabetes Care 2023;46:2232-9. PMCID:PMC10698223

[47] Ferrannini E.The stunned beta cell: a brief history.Cell Metab2010;11:349-52

[48] Bojsen-Møller KN,Madsbad S,Holst JJ.Hepatic insulin clearance in regulation of systemic insulin concentrations-role of carbohydrate and energy availability.Diabetes2018;67:2129-36

[49] Corkey BE.Banting lecture 2011: hyperinsulinemia: cause or consequence?.Diabetes2012;61:4-13 PMCID:PMC3237642

[50] Pories WJ.Diabetes: have we got it all wrong?.Diabetes Care2012;35:2438-42 PMCID:PMC3507594

[51] Tricò D,Mari A.Intrahepatic fat, irrespective of ethnicity, is associated with reduced endogenous insulin clearance and hepatic insulin resistance in obese youths: a cross-sectional and longitudinal study from the Yale Pediatric NAFLD cohort.Diabetes Obes Metab2020;22:1628-38 PMCID:PMC8174801

[52] Pivovarova O,Bobbert T.Hepatic insulin clearance is closely related to metabolic syndrome components.Diabetes Care2013;36:3779-85 PMCID:PMC3816867

[53] Smith K,Peeters W.Elevations in plasma glucagon are associated with reduced insulin clearance after ingestion of a mixed-macronutrient meal in people with and without type 2 diabetes.Diabetologia2024;Online ahead of print:

[54] Ghadieh HE,Muturi HT.Hyperinsulinemia drives hepatic insulin resistance in male mice with liver-specific Ceacam1 deletion independently of lipolysis.Metabolism2019;93:33-43 PMCID:PMC6401268

[55] Poy MN,Rezaei K.CEACAM1 regulates insulin clearance in liver.Nat Genet2002;30:270-6

[56] Russo L,Ghadieh HE.Liver-specific reconstitution of CEACAM1 reverses the metabolic abnormalities caused by its global deletion in male mice.Diabetologia2017;60:2463-74 PMCID:PMC5788286

[57] Watada H.Impaired insulin clearance as a cause rather than a consequence of insulin resistance.J Diabetes Investig2017;8:723-5 PMCID:PMC5668474

[58] Bril F,Orsak B.Relationship between disease severity, hyperinsulinemia, and impaired insulin clearance in patients with nonalcoholic steatohepatitis.Hepatology2014;59:2178-87

[59] Ramakrishnan SK,Al-Share QY.PPARα (peroxisome proliferator-activated receptor α) activation reduces hepatic CEACAM1 protein expression to regulate fatty acid oxidation during fasting-refeeding transition.J Biol Chem2016;291:8121-9 PMCID:PMC4825014

[60] Al-Share QY,Lester SG.Forced hepatic overexpression of CEACAM1 curtails diet-induced insulin resistance.Diabetes2015;64:2780-90 PMCID:PMC4512217

[61] Russo L,Ghanem SS.Role for hepatic CEACAM1 in regulating fatty acid metabolism along the adipocyte-hepatocyte axis.J Lipid Res2016;57:2163-75 PMCID:PMC5321226

[62] Lee W.The CEACAM1 expression is decreased in the liver of severely obese patients with or without diabetes.Diagn Pathol2011;6:40 PMCID:PMC3104481

[63] Zaidi S,Muturi HT.Loss of CEACAM1 in hepatocytes causes hepatic fibrosis.Eur J Clin Invest2024;54:e14177 PMCID:PMC11153018

[64] DeAngelis AM,Dai T.Carcinoembryonic antigen-related cell adhesion molecule 1: a link between insulin and lipid metabolism.Diabetes2008;57:2296-303 PMCID:PMC2518480

[65] Ghosh S,Patel PR.Mice with null mutation of Ceacam I develop nonalcoholic steatohepatitis.Hepat Med2010;2010:69-78 PMCID:PMC3177946

[66] Helal RA,Ghadieh HE.Regulation of hepatic fibrosis by carcinoembryonic antigen-related cell adhesion molecule 1.Metabolism2021;121:154801 PMCID:PMC8286970

[67] Xu E,Leung N.Targeted disruption of carcinoembryonic antigen-related cell adhesion molecule 1 promotes diet-induced hepatic steatosis and insulin resistance.Endocrinology2009;150:3503-12

[68] Brunt EM, Kleiner DE, Carpenter DH, et al; American Association for the Study of Liver Diseases NASH TASK FORce. NAFLD: reporting histologic findings in clinical practice. Hepatology 2021;73:2028-38.

[69] Friedman SL.Mechanisms of hepatic fibrogenesis.Gastroenterology2008;134:1655-69 PMCID:PMC2888539

[70] Jophlin LL,Chen C,Rockey DC.Hepatic stellate cells retain retinoid-laden lipid droplets after cellular transdifferentiation into activated myofibroblasts.Am J Physiol Gastrointest Liver Physiol2018;315:G713-21 PMCID:PMC6293250

[71] Hellemans K,Dittie A.Peroxisome proliferator-activated receptor-beta signaling contributes to enhanced proliferation of hepatic stellate cells.Gastroenterology2003;124:184-201

[72] Kostadinova R,Gouranton E.GW501516-activated PPARβ/δ promotes liver fibrosis via p38-JNK MAPK-induced hepatic stellate cell proliferation.Cell Biosci2012;2:34 PMCID:PMC3519722

[73] Berry DC.All-trans-retinoic acid represses obesity and insulin resistance by activating both peroxisome proliferation-activated receptor beta/delta and retinoic acid receptor.Mol Cell Biol2009;29:3286-96 PMCID:PMC2698724

[74] Forman BM,Evans RM.Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta.Proc Natl Acad Sci U S A1997;94:4312-7 PMCID:PMC20719

[75] Muturi HT,Asalla S.Conditional deletion of CEACAM1 in hepatic stellate cells causes their activation.Mol Metab2024;88:102010 PMCID:PMC11403062

[76] Muturi HT,Abdolahipour R.Loss of CEACAM1 in endothelial cells causes hepatic fibrosis.Metabolism2023;144:155562 PMCID:PMC10330196

[77] Wang Y,Cheon H,Stark GR.STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor.Proc Natl Acad Sci U S A2013;110:16975-80 PMCID:PMC3801081

[78] Najjar SM.CEACAM1 loss links inflammation to insulin resistance in obesity and non-alcoholic steatohepatitis (NASH).Semin Immunopathol2014;36:55-71 PMCID:PMC3946532

[79] Abou-Rjaily GA,May D.CEACAM1 modulates epidermal growth factor receptor-mediated cell proliferation.J Clin Invest2004;114:944-52 PMCID:PMC518664

[80] Lee SJ,Fedorova L.Development of nonalcoholic steatohepatitis in insulin-resistant liver-specific S503A carcinoembryonic antigen-related cell adhesion molecule 1 mutant mice.Gastroenterology2008;135:2084-95 PMCID:PMC2784638

[81] Lester SG,Ghanem SS.Hepatic CEACAM1 over-expression protects against diet-induced fibrosis and inflammation in white adipose tissue.Front Endocrinol (Lausanne)2015;6:116 PMCID:PMC4522571

[82] Muturi HT,Ghadieh HE.Insulin sensitivity is retained in mice with endothelial loss of carcinoembryonic antigen cell adhesion molecule 1.Cells2021;10:2093 PMCID:PMC8394790

[83] Ghadieh HE,Russo L.Exenatide induces carcinoembryonic antigen-related cell adhesion molecule 1 expression to prevent hepatic steatosis.Hepatol Commun2018;2:35-47 PMCID:PMC5776867

[84] Horst AK,Wagener C.CEACAM1 in liver injury, metabolic and immune regulation.Int J Mol Sci2018;19:3110 PMCID:PMC6213298

[85] Nakamura K,Kaldas FM.Hepatic CEACAM1 expression indicates donor liver quality and prevents early transplantation injury.J Clin Invest2020;130:2689-704 PMCID:PMC7190917

[86] Bowman TA,Kaw M.Caloric restriction reverses hepatic insulin resistance and steatosis in rats with low aerobic capacity.Endocrinology2010;151:5157-64 PMCID:PMC2954714