Exploration of Endocrine and Metabolic Diseases

Home
/
Exploration of Endocrine and Metabolic Diseases
/
Articles
/
Table 1

From: Diabetes mellitus and hepatosteatosis: a narrative review

Table 1. Main factors responsible for the pathogenesis of steatotic liver.

Factor	Description/Mechanism
Fat accumulation	> 5% fat in hepatocytes; due to an imbalance between input (diet, lipolysis, DNL) and output (VLDL secretion, β-oxidation)
Insulin resistance	Central to MASLD, it causes and worsens hepatic fat accumulation and glucose metabolism impairment
Hyperinsulinemia	Worsens MASLD by impairing glucose regulation and promoting fat storage
Genetic factors	Variants like PNPLA3 and TM6SF2 influence susceptibility and disease progression
Diet & environment	Excess caloric intake and environmental contributors promote steatosis
MASLD & T2DM coexistence	Linked with systemic inflammation, ER stress, mitochondrial dysfunction, and cytokine-mediated insulin signaling disruption
Gut microbiota	Alterations increase intestinal permeability and inflammation, contributing to MASLD and T2DM
Hepatokines	Low adiponectin and high fetuin-A levels contribute to insulin resistance

Return to article view

DNL: de novo lipogenesis; VLDL: very low-density lipoprotein; MASLD: metabolic dysfunction-associated steatotic liver disease; ER: endoplasmic reticulum; T2DM: Type 2 diabetes mellitus.

Declarations

Author contributions

MAK: Visualization, Writing—original draft, Writing—review & editing, Conceptualization. The author read and approved the submitted version.

Conflicts of interest

The author declares that there are no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

Publisher’s note

Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.

References

Huang DQ, Terrault NA, Tacke F, Gluud LL, Arrese M, Bugianesi E, et al. Global epidemiology of cirrhosis—aetiology, trends and predictions. Nat Rev Gastroenterol Hepatol. 2023;20:388–98. [DOI] [PubMed] [PMC]

Amini-Salehi E, Letafatkar N, Norouzi N, Joukar F, Habibi A, Javid M, et al. Global Prevalence of Nonalcoholic Fatty Liver Disease: An Updated Review Meta-Analysis comprising a Population of 78 million from 38 Countries. Arch Med Res. 2024;55:103043. [DOI] [PubMed]

Younossi ZM, Golabi P, Paik JM, Henry A, Van Dongen C, Henry L. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology. 2023;77:1335–47. [DOI] [PubMed] [PMC]

Liu J, Tian Y, Fu X, Mu C, Yao M, Ni Y, et al. Estimating global prevalence, incidence, and outcomes of non-alcoholic fatty liver disease from 2000 to 2021: systematic review and meta-analysis. Chin Med J (Engl). 2022;135:1682–91. [DOI] [PubMed] [PMC]

Tapper EB, Parikh ND. Diagnosis and Management of Cirrhosis and Its Complications: A Review. JAMA. 2023;329:1589–602. [DOI] [PubMed] [PMC]

Caussy C, Aubin A, Loomba R. The Relationship Between Type 2 Diabetes, NAFLD, and Cardiovascular Risk. Curr Diab Rep. 2021;21:15. [DOI] [PubMed] [PMC]

En Li Cho E, Ang CZ, Quek J, Fu CE, Lim LKE, Heng ZEQ, et al. Global prevalence of non-alcoholic fatty liver disease in type 2 diabetes mellitus: an updated systematic review and meta-analysis. Gut. 2023;72:2138–48. [DOI] [PubMed]

Lomonaco R, Godinez Leiva E, Bril F, Shrestha S, Mansour L, Budd J, et al. Advanced Liver Fibrosis Is Common in Patients With Type 2 Diabetes Followed in the Outpatient Setting: The Need for Systematic Screening. Diabetes Care. 2021;44:399–406. [DOI] [PubMed] [PMC]

Barb D, Repetto EM, Stokes ME, Shankar SS, Cusi K. Type 2 diabetes mellitus increases the risk of hepatic fibrosis in individuals with obesity and nonalcoholic fatty liver disease. Obesity (Silver Spring). 2021;29:1950–60. [DOI] [PubMed] [PMC]

10.

Yang B, Lu L, Zhou D, Fan W, Barbier-Torres L, Steggerda J, et al. Regulatory network and interplay of hepatokines, stellakines, myokines and adipokines in nonalcoholic fatty liver diseases and nonalcoholic steatohepatitis. Front Endocrinol (Lausanne). 2022;13:1007944. [DOI] [PubMed] [PMC]

11.

Lambertz J, Weiskirchen S, Landert S, Weiskirchen R. Fructose: A Dietary Sugar in Crosstalk with Microbiota Contributing to the Development and Progression of Non-Alcoholic Liver Disease. Front Immunol. 2017;8:1159. [DOI] [PubMed] [PMC]

12.

Herman MA, Samuel VT. The Sweet Path to Metabolic Demise: Fructose and Lipid Synthesis. Trends Endocrinol Metab. 2016;27:719–30. [DOI] [PubMed] [PMC]

13.

Denechaud PD, Dentin R, Girard J, Postic C. Role of ChREBP in hepatic steatosis and insulin resistance. FEBS Lett. 2008;582:68–73. [DOI] [PubMed]

14.

Mohammad S, Thiemermann C. Role of Metabolic Endotoxemia in Systemic Inflammation and Potential Interventions. Front Immunol. 2021;11:594150. [DOI] [PubMed] [PMC]

15.

Janssen JAMJL. Hyperinsulinemia and Its Pivotal Role in Aging, Obesity, Type 2 Diabetes, Cardiovascular Disease and Cancer. Int J Mol Sci. 2021;22:7797. [DOI] [PubMed] [PMC]

16.

Softic S, Cohen DE, Kahn CR. Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease. Dig Dis Sci. 2016;61:1282–93. [DOI] [PubMed] [PMC]

17.

Roden M. Mechanisms of Disease: hepatic steatosis in type 2 diabetes—pathogenesis and clinical relevance. Nat Clin Pract Endocrinol Metab. 2006;2:335–48. [DOI] [PubMed]

18.

Sundaram SS, Halbower A, Pan Z, Robbins K, Capocelli KE, Klawitter J, et al. Nocturnal hypoxia-induced oxidative stress promotes progression of pediatric non-alcoholic fatty liver disease. J Hepatol. 2016;65:560–9. [DOI] [PubMed] [PMC]

19.

Heida A, Gruben N, Catrysse L, Koehorst M, Koster M, Kloosterhuis NJ, et al. The hepatocyte IKK:NF-κB axis promotes liver steatosis by stimulating de novo lipogenesis and cholesterol synthesis. Mol Metab. 2021;54:101349. [DOI] [PubMed] [PMC]

20.

Branković M, Jovanović I, Dukić M, Radonjić T, Oprić S, Klašnja S, et al. Lipotoxicity as the Leading Cause of Non-Alcoholic Steatohepatitis. Int J Mol Sci. 2022;23:5146. [DOI] [PubMed] [PMC]

21.

Luukkonen PK, Zhou Y, Sädevirta S, Leivonen M, Arola J, Orešič M, et al. Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease. J Hepatol. 2016;64:1167–75. [DOI] [PubMed]

22.

Biondi G, Marrano N, Borrelli A, Rella M, Palma G, Calderoni I, et al. Adipose Tissue Secretion Pattern Influences β-Cell Wellness in the Transition from Obesity to Type 2 Diabetes. Int J Mol Sci. 2022;23:5522. [DOI] [PubMed] [PMC]

23.

Grzelka-Woźniak A, Uruska A, Szymańska-Garbacz E, Araszkiewicz A, Jabłkowski M, Czupryniak L, et al. Indirect insulin resistance markers are associated with nonalcoholic fatty liver disease in type 1 diabetes. Pol Arch Intern Med. 2023;133:16404. [DOI] [PubMed]

24.

Smith GI, Polidori DC, Yoshino M, Kearney ML, Patterson BW, Mittendorfer B, et al. Influence of adiposity, insulin resistance, and intrahepatic triglyceride content on insulin kinetics. J Clin Invest. 2020;130:3305–14. [DOI] [PubMed] [PMC]

25.

Suleiman M, Marselli L, Cnop M, Eizirik DL, De Luca C, Femia FR, et al. The Role of Beta Cell Recovery in Type 2 Diabetes Remission. Int J Mol Sci. 2022;23:7435. [DOI] [PubMed] [PMC]

26.

Mori K, Emoto M, Inaba M. Fetuin-A: a multifunctional protein. Recent Pat Endocr Metab Immune Drug Discov. 2011;5:124–46. [DOI] [PubMed]

27.

Brandon AE, Liao BM, Diakanastasis B, Parker BL, Raddatz K, McManus SA, et al. Protein Kinase C Epsilon Deletion in Adipose Tissue, but Not in Liver, Improves Glucose Tolerance. Cell Metab. 2019;29:183–91.e7. [DOI] [PubMed]

28.

Birkenfeld AL, Shulman GI. Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes. Hepatology. 2014;59:713–23. [DOI] [PubMed] [PMC]

29.

Cusi K. Treatment of patients with type 2 diabetes and non-alcoholic fatty liver disease: current approaches and future directions. Diabetologia. 2016;59:1112–20. [DOI] [PubMed] [PMC]

30.

Bornfeldt KE, Tabas I. Insulin resistance, hyperglycemia, and atherosclerosis. Cell Metab. 2011;14:575–85. [DOI] [PubMed] [PMC]

31.

Foretz M, Even PC, Viollet B. AMPK Activation Reduces Hepatic Lipid Content by Increasing Fat Oxidation In Vivo. Int J Mol Sci. 2018;19:2826. [DOI] [PubMed] [PMC]

32.

Meroni M, Longo M, Tria G, Dongiovanni P. Genetics Is of the Essence to Face NAFLD. Biomedicines. 2021;9:1359. [DOI] [PubMed] [PMC]

33.

Liu DJ, Peloso GM, Yu H, Butterworth AS, Wang X, Mahajan A, et al.; Charge Diabetes Working Group; EPIC-InterAct Consortium; EPIC-CVD Consortium; GOLD Consortium; VA Million Veteran Program; Howson JMM, Danesh J, McCarthy MI, Cowan CA, Abecasis G, Deloukas P, et al. Exome-wide association study of plasma lipids in > 300,000 individuals. Nat Genet. 2017;49:1758–66. [DOI] [PubMed] [PMC]

34.

Sharma D, Mandal P. NAFLD: genetics and its clinical implications. Clin Res Hepatol Gastroenterol. 2022;46:102003. [DOI] [PubMed]

35.

Stefan N, Cusi K. A global view of the interplay between non-alcoholic fatty liver disease and diabetes. Lancet Diabetes Endocrinol. 2022;10:284–96. [DOI] [PubMed]

36.

Shabalala SC, Dludla PV, Mabasa L, Kappo AP, Basson AK, Pheiffer C, et al. The effect of adiponectin in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and the potential role of polyphenols in the modulation of adiponectin signaling. Biomed Pharmacother. 2020;131:110785. [DOI] [PubMed]

37.

Junker AE, Gluud L, Holst JJ, Knop FK, Vilsbøll T. Diabetic and nondiabetic patients with nonalcoholic fatty liver disease have an impaired incretin effect and fasting hyperglucagonaemia. J Intern Med. 2016;279:485–93. [DOI] [PubMed]

38.

Saad MJA, Santos A, Prada PO. Linking Gut Microbiota and Inflammation to Obesity and Insulin Resistance. Physiology (Bethesda). 2016;31:283–93. [DOI] [PubMed]

39.

Ebrahimzadeh Leylabadlo H, Samadi Kafil H, Farajnia S, Shanehbandi D, Yaghoub Moaddab S, Feizabadi MM, et al. Gut microbiota in nonalcoholic fatty liver diseases with and without type-2 diabetes mellitus. Eur J Gastroenterol Hepatol. 2021;33:e548–54. [DOI] [PubMed]

40.

Loomba R, Seguritan V, Li W, Long T, Klitgord N, Bhatt A, et al. Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease. Cell Metab. 2017;25:1054–62.e5. [DOI] [PubMed] [PMC]

41.

Aron-Wisnewsky J, Vigliotti C, Witjes J, Le P, Holleboom AG, Verheij J, et al. Gut microbiota and human NAFLD: disentangling microbial signatures from metabolic disorders. Nat Rev Gastroenterol Hepatol. 2020;17:279–97. [DOI] [PubMed]

42.

Schiattarella GG, Sannino A, Toscano E, Giugliano G, Gargiulo G, Franzone A, et al. Gut microbe-generated metabolite trimethylamine-N-oxide as cardiovascular risk biomarker: a systematic review and dose-response meta-analysis. Eur Heart J. 2017;38:2948–56. [DOI] [PubMed]

43.

Qi J, You T, Li J, Pan T, Xiang L, Han Y, et al. Circulating trimethylamine N-oxide and the risk of cardiovascular diseases: a systematic review and meta-analysis of 11 prospective cohort studies. J Cell Mol Med. 2018;22:185–94. [DOI] [PubMed] [PMC]

44.

Adiels M, Olofsson SO, Taskinen MR, Borén J. Overproduction of very low-density lipoproteins is the hallmark of the dyslipidemia in the metabolic syndrome. Arterioscler Thromb Vasc Biol. 2008;28:1225–36. [DOI] [PubMed]

45.

Brouwers MCGJ, Simons N, Stehouwer CDA, Isaacs A. Non-alcoholic fatty liver disease and cardiovascular disease: assessing the evidence for causality. Diabetologia. 2020;63:253–60. [DOI] [PubMed] [PMC]

46.

Vaughan DE. PAI-1 and atherothrombosis. J Thromb Haemost. 2005;3:1879–83. [DOI] [PubMed]

47.

Biondi-Zoccai GGL, Abbate A, Liuzzo G, Biasucci LM. Atherothrombosis, inflammation, and diabetes. J Am Coll Cardiol. 2003;41:1071–7. [DOI] [PubMed]

48.

Hernaez R, Lazo M, Bonekamp S, Kamel I, Brancati FL, Guallar E, et al. Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis. Hepatology. 2011;54:1082–90. [DOI] [PubMed] [PMC]

49.

Mottin CC, Moretto M, Padoin AV, Swarowsky AM, Toneto MG, Glock L, et al. The role of ultrasound in the diagnosis of hepatic steatosis in morbidly obese patients. Obes Surg. 2004;14:635–7. [DOI] [PubMed]

50.

Karlas T, Petroff D, Sasso M, Fan JG, Mi YQ, de Lédinghen V, et al. Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis. J Hepatol. 2017;66:1022–30. [DOI] [PubMed]

51.

Nogami A, Iwaki M, Kobayashi T, Honda Y, Ogawa Y, Imajo K, et al. Real-world assessment of SmartExam, a novel FibroScan computational method: A retrospective single-center cohort study. J Gastroenterol Hepatol. 2023;38:321–9. [DOI] [PubMed]

52.

Guiu B, Petit JM, Loffroy R, Ben Salem D, Aho S, Masson D, et al. Quantification of liver fat content: comparison of triple-echo chemical shift gradient-echo imaging and in vivo proton MR spectroscopy. Radiology. 2009;250:95–102. [DOI] [PubMed]

53.

Bohte AE, van Werven JR, Bipat S, Stoker J. The diagnostic accuracy of US, CT, MRI and 1H-MRS for the evaluation of hepatic steatosis compared with liver biopsy: a meta-analysis. Eur Radiol. 2011;21:87–97. [DOI] [PubMed] [PMC]

54.

Starekova J, Reeder SB. Liver fat quantification: where do we stand? Abdom Radiol (NY). 2020;45:3386–99. [DOI] [PubMed] [PMC]

55.

Caussy C, Brissot J, Singh S, Bassirian S, Hernandez C, Bettencourt R, et al. Prospective, Same-Day, Direct Comparison of Controlled Attenuation Parameter With the M vs the XL Probe in Patients With Nonalcoholic Fatty Liver Disease, Using Magnetic Resonance Imaging-Proton Density Fat Fraction as the Standard. Clin Gastroenterol Hepatol. 2020;18:1842–50.e6. [DOI] [PubMed] [PMC]

56.

Hsu C, Caussy C, Imajo K, Chen J, Singh S, Kaulback K, et al. Magnetic Resonance vs Transient Elastography Analysis of Patients With Nonalcoholic Fatty Liver Disease: A Systematic Review and Pooled Analysis of Individual Participants. Clin Gastroenterol Hepatol. 2019;17:630–7.e8. [DOI] [PubMed] [PMC]

57.

Tapper EB, Challies T, Nasser I, Afdhal NH, Lai M. The Performance of Vibration Controlled Transient Elastography in a US Cohort of Patients With Nonalcoholic Fatty Liver Disease. Am J Gastroenterol. 2016;111:677–84. [DOI] [PubMed] [PMC]

58.

Castera L, Vilgrain V, Angulo P. Noninvasive evaluation of NAFLD. Nat Rev Gastroenterol Hepatol. 2013;10:666–75. [DOI] [PubMed]

59.

Friedrich-Rust M, Ong M, Martens S, Sarrazin C, Bojunga J, Zeuzem S, et al. Performance of transient elastography for the staging of liver fibrosis: a meta-analysis. Gastroenterology. 2008;134:960–74. [DOI] [PubMed]

60.

Wong VW, Vergniol J, Wong GL, Foucher J, Chan HL, Le Bail B, et al. Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease. Hepatology. 2010;51:454–62. [DOI] [PubMed]

61.

European Association for the Study of the Liver; European Association for the Study of Diabetes; European Association for the Study of Obesity. EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD): Executive Summary. Diabetologia. 2024;67:2375–92. [DOI] [PubMed] [PMC]

62.

Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003;38:518–26. [DOI] [PubMed]

63.

Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45:846–54. [DOI] [PubMed]

64.

European Association for the Study of the Liver. EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis—2021 update. J Hepatol. 2021;75:659–89. [DOI] [PubMed]

65.

McPherson S, Hardy T, Dufour JF, Petta S, Romero-Gomez M, Allison M, et al. Age as a Confounding Factor for the Accurate Non-Invasive Diagnosis of Advanced NAFLD Fibrosis. Am J Gastroenterol. 2017;112:740–51. [DOI] [PubMed] [PMC]

66.

Rosenberg WMC, Voelker M, Thiel R, Becka M, Burt A, Schuppan D, et al.; European Liver Fibrosis Group. Serum markers detect the presence of liver fibrosis: a cohort study. Gastroenterology. 2004;127:1704–13. [DOI] [PubMed]

67.

Hinkson A, Lally H, Gibson H, Jones R, Rowe IA, Shinkins B, et al. Meta-analysis: Enhanced liver fibrosis test to identify hepatic fibrosis in chronic liver diseases. Aliment Pharmacol Ther. 2023;57:750–62. [DOI] [PubMed]

68.

Daniels SJ, Leeming DJ, Eslam M, Hashem AM, Nielsen MJ, Krag A, et al. ADAPT: An Algorithm Incorporating PRO-C3 Accurately Identifies Patients With NAFLD and Advanced Fibrosis. Hepatology. 2019;69:1075–86. [DOI] [PubMed]

69.

Eslam M, Wong GL, Hashem AM, Chan HL, Nielsen MJ, Leeming DJ, et al. A Sequential Algorithm Combining ADAPT and Liver Stiffness Can Stage Metabolic-Associated Fatty Liver Disease in Hospital-Based and Primary Care Patients. Am J Gastroenterol. 2021;116:984–93. [DOI] [PubMed]

70.

Chan WK, Chuah KH, Rajaram RB, Lim LL, Ratnasingam J, Vethakkan SR. Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A State-of-the-Art Review. J Obes Metab Syndr. 2023;32:197–213. [DOI] [PubMed] [PMC]

71.

Yeh ML, Huang JF, Dai CY, Huang CF, Yu ML, Chuang WL. Metabolic dysfunction-associated steatotic liver disease and diabetes: the cross-talk between hepatologist and diabetologist. Expert Rev Gastroenterol Hepatol. 2024;18:431–9. [DOI] [PubMed]

72.

Ciardullo S, Vergani M, Perseghin G. Nonalcoholic Fatty Liver Disease in Patients with Type 2 Diabetes: Screening, Diagnosis, and Treatment. J Clin Med. 2023;12:5597. [DOI] [PubMed] [PMC]

73.

Huttasch M, Roden M, Kahl S. Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease? Metabolism. 2024;157:155937. [DOI] [PubMed]

74.

Alfieri CM, Molinari P, Cinque F, Vettoretti S, Cespiati A, Bignamini D, et al. What Not to Overlook in the Management of Patients with Type 2 Diabetes Mellitus: The Nephrological and Hepatological Perspectives. Int J Mol Sci. 2024;25:7728. [DOI] [PubMed] [PMC]

75.

Shah N, Sanyal AJ. A Pragmatic Management Approach for Metabolic Dysfunction-Associated Steatosis and Steatohepatitis. Am J Gastroenterol. 2025;120:75–82. [DOI] [PubMed]

76.

Jeong BK, Choi WI, Choi W, Moon J, Lee WH, Choi C, et al. A male mouse model for metabolic dysfunction-associated steatotic liver disease and hepatocellular carcinoma. Nat Commun. 2024;15:6506. [DOI] [PubMed] [PMC]

77.

Qi X, Li J, Caussy C, Teng GJ, Loomba R. Epidemiology, screening, and co-management of type 2 diabetes mellitus and metabolic dysfunction-associated steatotic liver disease. Hepatology. 2024;[Epub ahead of print]. [DOI] [PubMed]

78.

Koullias E, Papavdi M, Koskinas J, Deutsch M, Thanopoulou A. Targeting Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): Available and Future Pharmaceutical Options. Cureus. 2025;17:e76716. [DOI] [PubMed] [PMC]

79.

Alkhouri N, Noureddin M. Management strategies for metabolic dysfunction-associated steatotic liver disease (MASLD). Am J Manag Care. 2024;30:S159–74. [DOI] [PubMed]

80.

Targher G, Mantovani A, Byrne CD, Tilg H. Recent advances in incretin-based therapy for MASLD: from single to dual or triple incretin receptor agonists. Gut. 2025;74:487–97. [DOI] [PubMed]

81.

Zhang X, Lau HC, Yu J. Pharmacological treatment for metabolic dysfunction-associated steatotic liver disease and related disorders: Current and emerging therapeutic options. Pharmacol Rev. 2025;77:100018. [DOI] [PubMed]

82.

Francque SM, Bedossa P, Ratziu V, Anstee QM, Bugianesi E, Sanyal AJ, et al.; NATIVE Study Group. A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH. N Engl J Med. 2021;385:1547–58. [DOI] [PubMed]

83.

Lin RT, Sun QM, Xin X, Ng CH, Valenti L, Hu YY, et al. Comparative efficacy of THR-β agonists, FGF-21 analogues, GLP-1R agonists, GLP-1-based polyagonists, and Pan-PPAR agonists for MASLD: A systematic review and network meta-analysis. Metabolism. 2024;161:156043. [DOI] [PubMed]

84.

Ratziu V, de Guevara L, Safadi R, Poordad F, Fuster F, Flores-Figueroa J, et al. Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial. Nat Med. 2021;27:1825–35. [DOI] [PubMed] [PMC]

85.

Amin NB, Carvajal-Gonzalez S, Purkal J, Zhu T, Crowley C, Perez S, et al. Targeting diacylglycerol acyltransferase 2 for the treatment of nonalcoholic steatohepatitis. Sci Transl Med. 2019;11:eaav9701. [DOI] [PubMed]

86.

Lefere S, Puengel T, Hundertmark J, Penners C, Frank AK, Guillot A, et al. Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages^☆. J Hepatol. 2020;73:757–70. [DOI] [PubMed]

87.

Watanabe M, Houten SM, Wang L, Moschetta A, Mangelsdorf DJ, Heyman RA, et al. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest. 2004;113:1408–18. [DOI] [PubMed] [PMC]

88.

Caron S, Huaman Samanez C, Dehondt H, Ploton M, Briand O, Lien F, et al. Farnesoid X receptor inhibits the transcriptional activity of carbohydrate response element binding protein in human hepatocytes. Mol Cell Biol. 2013;33:2202–11. [DOI] [PubMed] [PMC]

89.

Finn PD, Rodriguez D, Kohler J, Jiang Z, Wan S, Blanco E, et al. Intestinal TGR5 agonism improves hepatic steatosis and insulin sensitivity in Western diet-fed mice. Am J Physiol Gastrointest Liver Physiol. 2019;316:G412–24. [DOI] [PubMed] [PMC]

90.

Thomas C, Gioiello A, Noriega L, Strehle A, Oury J, Rizzo G, et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 2009;10:167–77. [DOI] [PubMed] [PMC]