Anti-Inflammatory and Therapeutic Effects of a Novel Small-Molecule Inhibitor of Inflammation in a Male C57BL/6J Mouse Model of Obesity-Induced NAFLD/MAFLD

References

• Clark JM. The epidemiology of nonalcoholic fatty liver disease in adults. J Clin Gastroenterol. 2009;40(1):S5–S10.
   Google Scholar
• Zelber-Sagi S, Nitzan-Kaluski D, Halpern Z, Oren R. Prevalence of primary non-alcoholic fatty liver disease in a population-based study and its association with biochemical and anthropometric measures. Liver Int. 2006;26(7):856–863. doi:10.1111/j.1478-3231.2006.01311.x
   PubMed Web of Science ®Google Scholar
• Younossi Z, Anstee QM, Marietti M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15(1):11–20. doi:10.1038/nrgastro.2017.109
   PubMed Web of Science ®Google Scholar
• Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73–84. doi:10.1002/hep.28431
   PubMed Web of Science ®Google Scholar
• El-Serag HB, Kanwal F. Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go? Hepatology. 2014;60(5):1767–1775. doi:10.1002/hep.27222
   PubMed Web of Science ®Google Scholar
• Fabbrini E, Mohammed BS, Magkos F, Korenblat KM, Patterson BW, Klein S. Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology. 2008;134(2):424–431. doi:10.1053/j.gastro.2007.11.038
   PubMed Web of Science ®Google Scholar
• Marra F, Svegliati-Baroni G. Lipotoxicity and the gut-liver axis in NASH pathogenesis. J Hepatol. 2018;68(2):280–295. doi:10.1016/j.jhep.2017.11.014
   PubMed Web of Science ®Google Scholar
• Jia L, Vianna CR, Fukuda M, et al. Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance. Nat Commun. 2014;5(1):3878. doi:10.1038/ncomms4878
   PubMedGoogle Scholar
• Rogero MM, Calder PC. Obesity, inflammation, toll-like receptor 4 and fatty acids. Nutrients. 2018;10(4):432. doi:10.3390/nu10040432
   PubMed Web of Science ®Google Scholar
• Lancaster GI, Langley KG, Berglund NA, et al. Evidence that TLR4 is not a receptor for saturated fatty acids but mediates lipid-induced inflammation by reprogramming macrophage metabolism. Cell Metab. 2018;27(5):1096–110 e5. doi:10.1016/j.cmet.2018.03.014
   PubMed Web of Science ®Google Scholar
• Patton A, Church T, Wilson C, et al. Phenylmethimazole abrogates diet-induced inflammation, glucose intolerance and NAFLD. J Endocrinol. 2018;237(3):337–351. doi:10.1530/JOE-18-0078
   PubMed Web of Science ®Google Scholar
• Feingold KR, Grunfeld C. Tumor necrosis factor-alpha stimulates hepatic lipogenesis in the rat in vivo. J Clin Invest. 1987;80(1):184–190. doi:10.1172/JCI113046
   PubMed Web of Science ®Google Scholar
• Grunfeld C, Verdier JA, Neese R, Moser AH, Feingold KR. Mechanisms by which tumor necrosis factor stimulates hepatic fatty acid synthesis in vivo. J Lipid Res. 1988;29(10):1327–1335. doi:10.1016/S0022-2275(20)38435-2
   PubMed Web of Science ®Google Scholar
• Grunfeld C, Dinarello CA, Feingold KR. Tumor necrosis factor-alpha, interleukin-1, and interferon alpha stimulate triglyceride synthesis in HepG2 cells. Metabolism. 1991;40(9):894–898. doi:10.1016/0026-0495(91)90062-2
   PubMed Web of Science ®Google Scholar
• Feingold KR, Adi S, Staprans I, et al. Diet affects the mechanisms by which TNF stimulates hepatic triglyceride production. Am J Physiol. 1990;259(2 Pt 1):E177–E184. doi:10.1152/ajpendo.1990.259.2.E177
   PubMedGoogle Scholar
• Feingold KR, Staprans I, Memon RA, et al. Endotoxin rapidly induces changes in lipid metabolism that produce hypertriglyceridemia: low doses stimulate hepatic triglyceride production while high doses inhibit clearance. J Lipid Res. 1992;33(12):1765–1776. doi:10.1016/S0022-2275(20)41334-3
   PubMed Web of Science ®Google Scholar
• Mass Sanchez PB, Krizanac M, Weiskirchen R, Asimakopoulos A. Understanding the role of perilipin 5 in non-alcoholic fatty liver disease and its role in hepatocellular carcinoma: a review of novel insights. Int J Mol Sci. 2021;22(10):5284. doi:10.3390/ijms22105284
   PubMed Web of Science ®Google Scholar
• Zhang X, Zhi Y, Zan X, et al. Immune response gene 1 deficiency aggravates high fat diet-induced nonalcoholic fatty liver disease via promotion of redox-sensitive AKT suppression. Biochim Biophys Acta Mol Basis Dis. 2023;1869(4):166656. doi:10.1016/j.bbadis.2023.166656
   PubMed Web of Science ®Google Scholar
• Azzimato V, Chen P, Barreby E, et al. Hepatic miR-144 Drives Fumarase Activity Preventing NRF2 Activation During Obesity. Gastroenterology. 2021;161(6):1982–97 e11. doi:10.1053/j.gastro.2021.08.030
   PubMed Web of Science ®Google Scholar
• Moschen AR, Kaser S, Tilg H. Non-alcoholic steatohepatitis: a microbiota-driven disease. Trends Endocrinol Metab. 2013;24(11):537–545. doi:10.1016/j.tem.2013.05.009
   PubMed Web of Science ®Google Scholar
• Kirpich IA, Parajuli D, McClain CJ. Microbiome in NAFLD and ALD. Clin Liver Dis. 2015;6(3):55–58. doi:10.1002/cld.494
   Google Scholar
• Gangarapu V, Yildiz K, Ince AT, Baysal B. Role of gut microbiota: obesity and NAFLD. Turk J Gastroenterol. 2014;25(2):133–140. doi:10.5152/tjg.2014.7886
   Web of Science ®Google Scholar
• Kim KA, Gu W, Lee IA, Joh EH, Kim DH. High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway. PLoS One. 2012;7(10):e47713. doi:10.1371/journal.pone.0047713
   PubMed Web of Science ®Google Scholar
• Jin C, Flavell RA. Innate sensors of pathogen and stress: linking inflammation to obesity. J Allergy Clin Immunol. 2013;132(2):287–294. doi:10.1016/j.jaci.2013.06.022
   PubMed Web of Science ®Google Scholar
• Cani PD, Amar J, Iglesias MA, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007;56(7):1761–1772. doi:10.2337/db06-1491
   PubMed Web of Science ®Google Scholar
• Cani PD, Bibiloni R, Knauf C, et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes. 2008;57(6):1470–1481. doi:10.2337/db07-1403
   PubMed Web of Science ®Google Scholar
• Harte AL, da Silva NF, Creely SJ, et al. Elevated endotoxin levels in non-alcoholic fatty liver disease. J Inflamm. 2010;7(1):15. doi:10.1186/1476-9255-7-15
   Google Scholar
• Compare D, Coccoli P, Rocco A, et al. Gut--liver axis: the impact of gut microbiota on non alcoholic fatty liver disease. Nutr Metab Cardiovasc Dis. 2012;22(6):471–476. doi:10.1016/j.numecd.2012.02.007
   PubMed Web of Science ®Google Scholar
• Aron-Wisnewsky J, Gaborit B, Dutour A, Clement K. Gut microbiota and non-alcoholic fatty liver disease: new insights. Clin Microbiol Infect. 2013;19(4):338–348. doi:10.1111/1469-0691.12140
   PubMed Web of Science ®Google Scholar
• Han X, Fink MP, Yang R, Delude RL. Increased iNOS activity is essential for intestinal epithelial tight junction dysfunction in endotoxemic mice. Shock. 2004;21(3):261–270. doi:10.1097/01.shk.0000112346.38599.10
   PubMed Web of Science ®Google Scholar
• Chin AC, Flynn AN, Fedwick JP, Buret AG. The role of caspase-3 in lipopolysaccharide-mediated disruption of intestinal epithelial tight junctions. Can J Physiol Pharmacol. 2006;84(10):1043–1050. doi:10.1139/y06-056
   PubMed Web of Science ®Google Scholar
• Lee B, Moon KM, Kim CY. Tight junction in the intestinal epithelium: its association with diseases and regulation by phytochemicals. J Immunol Res. 2018;2018:2645465. doi:10.1155/2018/2645465
   PubMed Web of Science ®Google Scholar
• Chelakkot C, Ghim J, Ryu SH. Mechanisms regulating intestinal barrier integrity and its pathological implications. Exp Mol Med. 2018;50(8):1–9. doi:10.1038/s12276-018-0126-x
   PubMed Web of Science ®Google Scholar
• Liangpunsakul S, Chalasani N. Lipid mediators of liver injury in nonalcoholic fatty liver disease. Am J Physiol Gastrointest Liver Physiol. 2019;316(1):G75–G81. doi:10.1152/ajpgi.00170.2018
   PubMed Web of Science ®Google Scholar
• Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010;52(5):1836–1846. doi:10.1002/hep.24001
   PubMed Web of Science ®Google Scholar
• Chen LL, Morcelle C, Cheng ZL, et al. Itaconate inhibits TET DNA dioxygenases to dampen inflammatory responses. Nat Cell Biol. 2022;24(3):353–363. doi:10.1038/s41556-022-00853-8
   PubMed Web of Science ®Google Scholar
• Mills EL, Ryan DG, Prag HA, et al. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature. 2018;556(7699):113–117. doi:10.1038/nature25986
   PubMed Web of Science ®Google Scholar
• O’Neill LAJ, Artyomov MN. Itaconate: the poster child of metabolic reprogramming in macrophage function. Nat Rev Immunol. 2019;19(5):273–281. doi:10.1038/s41577-019-0128-5
   PubMed Web of Science ®Google Scholar
• Oates JR, McKell MC, Moreno-Fernandez ME, et al. Macrophage function in the pathogenesis of non-alcoholic fatty liver disease: the mac attack. Front Immunol. 2019;10:2893. doi:10.3389/fimmu.2019.02893
   PubMed Web of Science ®Google Scholar
• Berge RK, Cacabelos D, Senaris R, et al. Hepatic steatosis induced in C57BL/6 mice by a non-ss oxidizable fatty acid analogue is associated with reduced plasma kynurenine metabolites and a modified hepatic NAD(+)/NADH ratio. Lipids Health Dis. 2020;19(1):94. doi:10.1186/s12944-020-01271-1
   PubMed Web of Science ®Google Scholar
• Yeung AW, Terentis AC, King NJ, Thomas SR. Role of indoleamine 2,3-dioxygenase in health and disease. Clin Sci. 2015;129(7):601–672.
   PubMed Web of Science ®Google Scholar
• Sumida Y, Yoneda M. Current and future pharmacological therapies for NAFLD/NASH. J Gastroenterol. 2018;53(3):362–376. doi:10.1007/s00535-017-1415-1
   PubMed Web of Science ®Google Scholar
• Sarwar R, Pierce N, Koppe S. Obesity and nonalcoholic fatty liver disease: current perspectives. Diabetes Metab Syndr Obes. 2018;11:533–542. doi:10.2147/DMSO.S146339
   PubMed Web of Science ®Google Scholar
• Wong VW, Chitturi S, Wong GL, Yu J, Chan HL, Farrell GC. Pathogenesis and novel treatment options for non-alcoholic steatohepatitis. Lancet Gastroenterol Hepatol. 2016;1(1):56–67. doi:10.1016/S2468-1253(16)30011-5
   PubMed Web of Science ®Google Scholar
• Sharma M, Premkumar M, Kulkarni AV, Kumar P, Reddy DN, Rao NP. Drugs for Non-alcoholic Steatohepatitis (NASH): quest for the Holy Grail. J Clin Transl Hepatol. 2021;9(1):40–50. doi:10.14218/JCTH.2020.00055
   PubMed Web of Science ®Google Scholar
• Lavine JE, Schwimmer JB, Van Natta ML, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA. 2011;305(16):1659–1668. doi:10.1001/jama.2011.520
   PubMed Web of Science ®Google Scholar
• Loomba R, Lutchman G, Kleiner DE, et al. Clinical trial: pilot study of metformin for the treatment of non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2009;29(2):172–182. doi:10.1111/j.1365-2036.2008.03869.x
   PubMed Web of Science ®Google Scholar
• Nair S, Diehl AM, Wiseman M, Farr GH, Perrillo RP. Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol Ther. 2004;20(1):23–28. doi:10.1111/j.1365-2036.2004.02025.x
   PubMed Web of Science ®Google Scholar
• Cusi K, Orsak B, Bril F, et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann Intern Med. 2016;165(5):305–315. doi:10.7326/M15-1774
   PubMed Web of Science ®Google Scholar
• Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355(22):2297–2307. doi:10.1056/NEJMoa060326
   PubMed Web of Science ®Google Scholar
• Aithal GP, Thomas JA, Kaye PV, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology. 2008;135(4):1176–1184. doi:10.1053/j.gastro.2008.06.047
   PubMed Web of Science ®Google Scholar
• Jastreboff AM, Kaplan LM, Frias JP, et al. Triple-hormone-receptor agonist retatrutide for obesity - a Phase 2 trial. N Engl J Med. 2023;389(6):514–526. doi:10.1056/NEJMoa2301972
   PubMed Web of Science ®Google Scholar
• Spengler EK, Loomba R. Recommendations for diagnosis, referral for liver biopsy, and treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Mayo Clin Proc. 2015;90(9):1233–1246. doi:10.1016/j.mayocp.2015.06.013
   PubMed Web of Science ®Google Scholar
• Dagia NM, Harii N, Meli AE, et al. Phenyl methimazole inhibits TNF-alpha-induced VCAM-1 expression in an IFN regulatory factor-1-dependent manner and reduces monocytic cell adhesion to endothelial cells. J Immunol. 2004;173(3):2041–2049. doi:10.4049/jimmunol.173.3.2041
   PubMed Web of Science ®Google Scholar
• McCall KD, Harii N, Lewis CJ, et al. High basal levels of functional Toll-Like Receptor 3 (TLR3) and non-cannonical wnt5a are expressed in Papillary Thyroid Cancer (PTC) and are coordinately decreased by phenylmethimazole together with cell proliferation and migration. Endocrinology. 2007;148(9):4226–4237. doi:10.1210/en.2007-0459
   PubMed Web of Science ®Google Scholar
• McCall KD, Holliday D, Dickerson E, et al. Phenylmethimazole blocks palmitate-mediated induction of inflammatory cytokine pathways in 3T3L1 adipocytes and RAW 264.7 macrophages. J Endocrinol. 2010;207(3):343–353. doi:10.1677/JOE-09-0370
   PubMed Web of Science ®Google Scholar
• McCall KD, Schmerr MJ, Thuma JR, et al. Phenylmethimazole suppresses dsRNA-induced cytotoxicity and inflammatory cytokines in murine pancreatic beta cells and blocks viral acceleration of type 1 diabetes in NOD mice. Molecules. 2013;18(4):3841–3858. doi:10.3390/molecules18043841
   PubMed Web of Science ®Google Scholar
• Schwartz AL, Malgor R, Dickerson E, et al. Phenylmethimazole decreases Toll-like receptor 3 and noncanonical Wnt5a expression in pancreatic cancer and melanoma together with tumor cell growth and migration. Clin Cancer Res. 2009;15(12):4114–4122. doi:10.1158/1078-0432.CCR-09-0005
   PubMed Web of Science ®Google Scholar
• Deosarkar SP, Bhatt P, Gillespie J, Goetz DJ, McCall KD. Inhibition of LPS-induced TLR4 signaling products in murine macrophages by phenylmethimazole: an assay methodology for screening potential phenylmethimazole analogs. Drug Dev Res. 2014;75(8):497–509. doi:10.1002/ddr.21231
   PubMed Web of Science ®Google Scholar
• Courreges MC, Kantake N, Goetz DJ, Schwartz FL, McCall KD. Phenylmethimazole blocks dsRNA-induced IRF3 nuclear translocation and homodimerization. Molecules. 2012;17(10):12365–12377. doi:10.3390/molecules171012365
   PubMed Web of Science ®Google Scholar
• Harii N, Lewis C, Vasko V, et al. Thyrocytes express a functional toll-like receptor 3(TLR3): overexpression can be induced by viral infection, reversed by Phenylmethimazole, and is associated with Hashimoto’s autoimmune thyroiditis. Mol Endocrinol. 2005;19(5):1231–1250. doi:10.1210/me.2004-0100
   PubMedGoogle Scholar
• Schwartz AL, Dickerson E, Dagia N, Malgor R, McCall KD. TLR signaling inhibitor, phenylmethimazole, in combination with tamoxifen inhibits human breast cancer cell viability and migration. Oncotarget. 2017;8(69):113295–113302. doi:10.18632/oncotarget.10358
   PubMedGoogle Scholar
• Gan SF, Wan JP, Pan YJ, Sun CR. Water-mediated multicomponent reaction: a facile and efficient synthesis of multisubstituted thiazolidine-2-thiones. Synlett. 2010;6:973–975.
   Google Scholar
• Hwang LL, Wang CH, Li TL, et al. Sex differences in high-fat diet-induced obesity, metabolic alterations and learning, and synaptic plasticity deficits in mice. Obesity. 2010;18(3):463–469. doi:10.1038/oby.2009.273
   PubMed Web of Science ®Google Scholar
• Benz V, Bloch M, Wardat S, et al. Sexual dimorphic regulation of body weight dynamics and adipose tissue lipolysis. PLoS One. 2012;7(5):e37794. doi:10.1371/journal.pone.0037794
   PubMed Web of Science ®Google Scholar
• Yang Y, Smith DL, Keating KD, Allison DB, Nagy TR. Variations in body weight, food intake and body composition after long-term high-fat diet feeding in C57BL/6J mice. Obesity. 2014;22(10):2147–2155. doi:10.1002/oby.20811
   PubMed Web of Science ®Google Scholar
• Pettersson US, Walden TB, Carlsson PO, Jansson L, Phillipson M, Maedler K. Female mice are protected against high-fat diet induced metabolic syndrome and increase the regulatory T cell population in adipose tissue. PLoS One. 2012;7(9):e46057. doi:10.1371/journal.pone.0046057
   PubMed Web of Science ®Google Scholar
• Stubbins RE, Najjar K, Holcomb VB, Hong J, Nunez NP. Oestrogen alters adipocyte biology and protects female mice from adipocyte inflammation and insulin resistance. Diabetes Obes Metab. 2012;14(1):58–66. doi:10.1111/j.1463-1326.2011.01488.x
   PubMed Web of Science ®Google Scholar
• Hill-Baskin AE, Markiewski MM, Buchner DA, et al. Diet-induced hepatocellular carcinoma in genetically predisposed mice. Hum Mol Genet. 2009;18(16):2975–2988. doi:10.1093/hmg/ddp236
   PubMed Web of Science ®Google Scholar
• VanSaun MN, Lee IK, Washington MK, Matrisian L, Gorden DL. High fat diet induced hepatic steatosis establishes a permissive microenvironment for colorectal metastases and promotes primary dysplasia in a murine model. Am J Pathol. 2009;175(1):355–364. doi:10.2353/ajpath.2009.080703
   PubMed Web of Science ®Google Scholar
• Nakamura A, Tajima K, Zolzaya K, et al. Protection from non-alcoholic steatohepatitis and liver tumourigenesis in high fat-fed insulin receptor substrate-1-knockout mice despite insulin resistance. Diabetologia. 2012;55(12):3382–3391. doi:10.1007/s00125-012-2703-1
   PubMed Web of Science ®Google Scholar
• Pan X, Wang P, Luo J, et al. Adipogenic changes of hepatocytes in a high-fat diet-induced fatty liver mice model and non-alcoholic fatty liver disease patients. Endocrine. 2014;48:834–847.
   PubMed Web of Science ®Google Scholar
• Fraulob JC, Ogg-Diamantino R, Fernandes-Santos C, Aguila MB, Mandarim-de-Lacerda CA. A mouse model of metabolic syndrome: insulin resistance, fatty liver and Non-Alcoholic Fatty Pancreas Disease (NAFPD) in C57BL/6 mice fed a high fat diet. J Clin Biochem Nutr. 2010;46(3):212–223. doi:10.3164/jcbn.09-83
   PubMed Web of Science ®Google Scholar
• Surwit RS, Kuhn CM, Cochrane C, McCubbin JA, Feinglos MN. Diet-induced type II diabetes in C57BL/6J mice. Diabetes. 1988;37(9):1163–1167. doi:10.2337/diab.37.9.1163
   PubMed Web of Science ®Google Scholar
• Surwit RS, Feinglos MN, Rodin J, et al. Differential effects of fat and sucrose on the development of obesity and diabetes in C57BL/6J and A/J mice. Metabolism. 1995;44(5):645–651. doi:10.1016/0026-0495(95)90123-X
   PubMed Web of Science ®Google Scholar
• Qiu L, List EO, Kopchick JJ. Differentially expressed proteins in the pancreas of diet-induced diabetic mice. Mol Cell Proteomics. 2005;4(9):1311–1318. doi:10.1074/mcp.M500016-MCP200
   PubMed Web of Science ®Google Scholar
• List EO, Berryman DE, Palmer AJ, et al. Analysis of mouse skin reveals proteins that are altered in a diet-induced diabetic state: a new method for detection of type 2 diabetes. Proteomics. 2007;7(7):1140–1149. doi:10.1002/pmic.200600641
   PubMed Web of Science ®Google Scholar
• Sun G, Jackson CV, Zimmerman K, et al. The FATZO mouse, a next generation model of type 2 diabetes, develops NAFLD and NASH when fed a Western diet supplemented with fructose. BMC Gastroenterol. 2019;19(1):41. doi:10.1186/s12876-019-0958-4
   PubMedGoogle Scholar
• Stubbins RE, Holcomb VB, Hong J, Nunez NP. Estrogen modulates abdominal adiposity and protects female mice from obesity and impaired glucose tolerance. Eur J Nutr. 2012;51(7):861–870. doi:10.1007/s00394-011-0266-4
   PubMed Web of Science ®Google Scholar
• Fu X, Xing L, Xu W, Shu J. Treatment with estrogen protects against ovariectomy-induced hepatic steatosis by increasing AQP7 expression. Mol Med Rep. 2016;14(1):425–431. doi:10.3892/mmr.2016.5236
   PubMed Web of Science ®Google Scholar
• Xin G, Qin S, Wang S, Wang X, Zhang Y, Wang J. Sex hormone affects the severity of non-alcoholic steatohepatitis through the MyD88-dependent IL-6 signaling pathway. Exp Biol Med. 2015;240(10):1279–1286. doi:10.1177/1535370215570189
   Web of Science ®Google Scholar
• Gao H, Bryzgalova G, Hedman E, et al. Long-term administration of estradiol decreases expression of hepatic lipogenic genes and improves insulin sensitivity in ob/ob mice: a possible mechanism is through direct regulation of signal transducer and activator of transcription 3. Mol Endocrinol. 2006;20(6):1287–1299. doi:10.1210/me.2006-0012
   PubMedGoogle Scholar
• Chow JD, Jones ME, Prelle K, Simpson ER, Boon WC. A selective estrogen receptor alpha agonist ameliorates hepatic steatosis in the male aromatase knockout mouse. J Endocrinol. 2011;210(3):323–334. doi:10.1530/JOE-10-0462
   PubMed Web of Science ®Google Scholar
• Paquette A, Wang D, Jankowski M, Gutkowska J, Lavoie JM. Effects of ovariectomy on PPAR alpha, SREBP-1c, and SCD-1 gene expression in the rat liver. Menopause. 2008;15(6):1169–1175. doi:10.1097/gme.0b013e31817b8159
   PubMed Web of Science ®Google Scholar
• Geary N, Asarian L, Korach KS, Pfaff DW, Ogawa S. Deficits in E2-dependent control of feeding, weight gain, and cholecystokinin satiation in ER-alpha null mice. Endocrinology. 2001;142(11):4751–4757. doi:10.1210/endo.142.11.8504
   PubMed Web of Science ®Google Scholar
• Jones ME, Thorburn AW, Britt KL, et al. Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity. Proc Natl Acad Sci U S A. 2000;97(23):12735–12740. doi:10.1073/pnas.97.23.12735
   PubMed Web of Science ®Google Scholar
• Cooke PS, Naaz A. Role of estrogens in adipocyte development and function. Exp Biol Med. 2004;229(11):1127–1135. doi:10.1177/153537020422901107
   PubMed Web of Science ®Google Scholar
• Monteiro R, Teixeira D, Calhau C. Estrogen signaling in metabolic inflammation. Mediators Inflamm. 2014;2014:615917. doi:10.1155/2014/615917
   PubMed Web of Science ®Google Scholar
• Lai YS, Chen WC, Kuo TC, et al. Mass-spectrometry-based serum metabolomics of a C57BL/6J mouse model of high-fat-diet-induced non-alcoholic fatty liver disease development. J Agric Food Chem. 2015;63(35):7873–7884. doi:10.1021/acs.jafc.5b02830
   PubMed Web of Science ®Google Scholar
• Gopal SS, Sukhdeo SV, Vallikannan B, Ponesakki G. Lutein ameliorates high-fat diet-induced obesity, fatty liver, and glucose intolerance in C57BL/6J mice. Phytother Res. 2023;37(1):329–341. doi:10.1002/ptr.7615
   PubMed Web of Science ®Google Scholar
• List EO, Palmer AJ, Berryman DE, Bower B, Kelder B, Kopchick JJ. Growth hormone improves body composition, fasting blood glucose, glucose tolerance and liver triacylglycerol in a mouse model of diet-induced obesity and type 2 diabetes. Diabetologia. 2009;52(8):1647–1655. doi:10.1007/s00125-009-1402-z
   PubMed Web of Science ®Google Scholar
• Mukai T, Egawa M, Takeuchi T, Yamashita H, Kusudo T. Silencing of FABP1 ameliorates hepatic steatosis, inflammation, and oxidative stress in mice with nonalcoholic fatty liver disease. FEBS Open Bio. 2017;7(7):1009–1016. doi:10.1002/2211-5463.12240
   PubMed Web of Science ®Google Scholar
• Ni X, Wang H. Silymarin attenuated hepatic steatosis through regulation of lipid metabolism and oxidative stress in a mouse model of nonalcoholic fatty liver disease (NAFLD). Am J Transl Res. 2016;8(2):1073–1081.
   PubMed Web of Science ®Google Scholar
• Salmon DM, Flatt JP. Effect of dietary fat content on the incidence of obesity among ad libitum fed mice. Int J Obes. 1985;9(6):443–449.
   PubMed Web of Science ®Google Scholar
• Zeybel M, Altay O, Arif M, et al. Combined metabolic activators therapy ameliorates liver fat in nonalcoholic fatty liver disease patients. Mol Syst Biol. 2021;17(10):e10459. doi:10.15252/msb.202110459
   PubMed Web of Science ®Google Scholar
• Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402–408. doi:10.1006/meth.2001.1262
   PubMed Web of Science ®Google Scholar
• Xu L, Liu W, Bai F, et al. Hepatic macrophage as a key player in fatty liver disease. Front Immunol. 2021;12:708978. doi:10.3389/fimmu.2021.708978
   PubMed Web of Science ®Google Scholar
• Ito M, Suzuki J, Tsujioka S, et al. Longitudinal analysis of murine steatohepatitis model induced by chronic exposure to high-fat diet. Hepatol Res. 2007;37(1):50–57. doi:10.1111/j.1872-034X.2007.00008.x
   PubMed Web of Science ®Google Scholar
• Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27(5):1047–1053. doi:10.2337/diacare.27.5.1047
   PubMed Web of Science ®Google Scholar
• Imes CC, Burke LE. The obesity epidemic: the United States as a cautionary tale for the rest of the world. Curr Epidemiol Rep. 2014;1(2):82–88. doi:10.1007/s40471-014-0012-6
   PubMedGoogle Scholar
• Haukeland JW, Konopski Z, Eggesbo HB, et al. Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol. 2009;44(7):853–860. doi:10.1080/00365520902845268
   PubMed Web of Science ®Google Scholar
• Ratziu V, Giral P, Jacqueminet S, et al. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology. 2008;135(1):100–110. doi:10.1053/j.gastro.2008.03.078
   PubMed Web of Science ®Google Scholar
• Eslami L, Merat S, Malekzadeh R, Nasseri-Moghaddam S, Aramin H. Statins for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Cochrane Database Syst Rev. 2013;12:CD008623.
   Google Scholar
• Xu H, Barnes GT, Yang Q, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112(12):1821–1830. doi:10.1172/JCI200319451
   PubMed Web of Science ®Google Scholar
• Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112(12):1796–1808. doi:10.1172/JCI200319246
   PubMed Web of Science ®Google Scholar
• Glass CK, Olefsky JM. Inflammation and lipid signaling in the etiology of insulin resistance. Cell Metab. 2012;15(5):635–645. doi:10.1016/j.cmet.2012.04.001
   PubMed Web of Science ®Google Scholar
• Davi G, Guagnano MT, Ciabattoni G, et al. Platelet activation in obese women: role of inflammation and oxidant stress. JAMA. 2002;288(16):2008–2014. doi:10.1001/jama.288.16.2008
   PubMed Web of Science ®Google Scholar
• Kriketos AD, Greenfield JR, Peake PW, et al. Inflammation, insulin resistance, and adiposity: a study of first-degree relatives of type 2 diabetic subjects. Diabetes Care. 2004;27(8):2033–2040. doi:10.2337/diacare.27.8.2033
   PubMed Web of Science ®Google Scholar
• Lemieux I, Pascot A, Prud’homme D, et al. Elevated C-reactive protein: another component of the atherothrombotic profile of abdominal obesity. Arterioscler Thromb Vasc Biol. 2001;21(6):961–967. doi:10.1161/01.ATV.21.6.961
   PubMed Web of Science ®Google Scholar
• Poitou C, Coussieu C, Rouault C, et al. Serum amyloid A: a marker of adiposity-induced low-grade inflammation but not of metabolic status. Obesity. 2006;14(2):309–318. doi:10.1038/oby.2006.40
   PubMed Web of Science ®Google Scholar
• Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest. 2005;115(5):1111–1119. doi:10.1172/JCI25102
   PubMed Web of Science ®Google Scholar
• Targher G, Arcaro G. Non-alcoholic fatty liver disease and increased risk of cardiovascular disease. Atherosclerosis. 2007;191(2):235–240. doi:10.1016/j.atherosclerosis.2006.08.021
   PubMed Web of Science ®Google Scholar
• Davis JE, Gabler NK, Walker-Daniels J, Spurlock ME. Tlr-4 deficiency selectively protects against obesity induced by diets high in saturated fat. Obesity. 2008;16(6):1248–1255. doi:10.1038/oby.2008.210
   PubMed Web of Science ®Google Scholar
• Pierre N, Deldicque L, Barbe C, Naslain D, Cani PD, Francaux M. Toll-like receptor 4 knockout mice are protected against endoplasmic reticulum stress induced by a high-fat diet. PLoS One. 2013;8(5):e65061. doi:10.1371/journal.pone.0065061
   PubMed Web of Science ®Google Scholar
• Sawada K, Ohtake T, Hasebe T, et al. Augmented hepatic Toll-like receptors by fatty acids trigger the pro-inflammatory state of non-alcoholic fatty liver disease in mice. Hepatol Res. 2014;44(8):920–934. doi:10.1111/hepr.12199
   PubMed Web of Science ®Google Scholar
• Frost RA, Nystrom GJ, Lang CH. Lipopolysaccharide regulates proinflammatory cytokine expression in mouse myoblasts and skeletal muscle. Am J Physiol Regul Integr Comp Physiol. 2002;283(3):R698–R709. doi:10.1152/ajpregu.00039.2002
   PubMed Web of Science ®Google Scholar
• Gustot T, Lemmers A, Moreno C, et al. Differential liver sensitization to toll-like receptor pathways in mice with alcoholic fatty liver. Hepatology. 2006;43(5):989–1000. doi:10.1002/hep.21138
   PubMed Web of Science ®Google Scholar
• Song MJ, Kim KH, Yoon JM, Kim JB. Activation of Toll-like receptor 4 is associated with insulin resistance in adipocytes. Biochem Biophys Res Commun. 2006;346(3):739–745. doi:10.1016/j.bbrc.2006.05.170
   PubMed Web of Science ®Google Scholar
• Frost RA, Nystrom GJ, Lang CH. Multiple Toll-like receptor ligands induce an IL-6 transcriptional response in skeletal myocytes. Am J Physiol Regul Integr Comp Physiol. 2006;290(3):R773–R784. doi:10.1152/ajpregu.00490.2005
   PubMed Web of Science ®Google Scholar
• Lang CH, Silvis C, Deshpande N, Nystrom G, Frost RA. Endotoxin stimulates in vivo expression of inflammatory cytokines tumor necrosis factor alpha, interleukin-1beta, −6, and high-mobility-group protein-1 in skeletal muscle. Shock. 2003;19(6):538–546. doi:10.1097/01.shk.0000055237.25446.80
   PubMed Web of Science ®Google Scholar
• Reyna SM, Ghosh S, Tantiwong P, et al. Elevated toll-like receptor 4 expression and signaling in muscle from insulin-resistant subjects. Diabetes. 2008;57(10):2595–2602. doi:10.2337/db08-0038
   PubMed Web of Science ®Google Scholar
• Radin MS, Sinha S, Bhatt BA, Dedousis N, O’Doherty RM. Inhibition or deletion of the lipopolysaccharide receptor Toll-like receptor-4 confers partial protection against lipid-induced insulin resistance in rodent skeletal muscle. Diabetologia. 2008;51(2):336–346. doi:10.1007/s00125-007-0861-3
   PubMed Web of Science ®Google Scholar
• Burgueno JF, Abreu MT. Epithelial Toll-like receptors and their role in gut homeostasis and disease. Nat Rev Gastroenterol Hepatol. 2020;17(5):263–278. doi:10.1038/s41575-019-0261-4
   PubMed Web of Science ®Google Scholar
• Jialal I, Kaur H, Devaraj S. Toll-like receptor status in obesity and metabolic syndrome: a translational perspective. J Clin Endocrinol Metab. 2014;99(1):39–48. doi:10.1210/jc.2013-3092
   PubMed Web of Science ®Google Scholar
• Miura K, Yang L, van Rooijen N, Brenner DA, Ohnishi H, Seki E. Toll-like receptor 2 and palmitic acid cooperatively contribute to the development of nonalcoholic steatohepatitis through inflammasome activation in mice. Hepatology. 2013;57(2):577–589. doi:10.1002/hep.26081
   PubMed Web of Science ®Google Scholar
• Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest. 2006;116(11):3015–3025. doi:10.1172/JCI28898
   PubMed Web of Science ®Google Scholar
• Erridge C, Attina T, Spickett CM, Webb DJ. A high-fat meal induces low-grade endotoxemia: evidence of a novel mechanism of postprandial inflammation. Am J Clin Nutr. 2007;86(5):1286–1292. doi:10.1093/ajcn/86.5.1286
   PubMed Web of Science ®Google Scholar
• Creely SJ, McTernan PG, Kusminski CM, et al. Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. Am J Physiol Endocrinol Metab. 2007;292(3):E740–E747. doi:10.1152/ajpendo.00302.2006
   PubMed Web of Science ®Google Scholar
• Mehta NN, McGillicuddy FC, Anderson PD, et al. Experimental endotoxemia induces adipose inflammation and insulin resistance in humans. Diabetes. 2009;59(1):172–181. doi:10.2337/db09-0367
   PubMed Web of Science ®Google Scholar
• Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature. 2006;444(7122):1022–1023. doi:10.1038/4441022a
   PubMed Web of Science ®Google Scholar
• Bajzer M, Seeley RJ. Physiology: obesity and gut flora. Nature. 2006;444(7122):1009–1010. doi:10.1038/4441009a
   PubMed Web of Science ®Google Scholar
• de La Serre CB, Ellis CL, Lee J, Hartman AL, Rutledge JC, Raybould HE. Propensity to high-fat diet-induced obesity in rats is associated with changes in the gut microbiota and gut inflammation. Am J Physiol Gastrointest Liver Physiol. 2010;299(2):G440–G448. doi:10.1152/ajpgi.00098.2010
   PubMed Web of Science ®Google Scholar
• Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444(7122):1027–1031. doi:10.1038/nature05414
   PubMed Web of Science ®Google Scholar
• Kopp A, Buechler C, Neumeier M, et al. Innate immunity and adipocyte function: ligand-specific activation of multiple toll-like receptors modulates cytokine, adipokine, and chemokine secretion in adipocytes. Obesity. 2009;17(4):648–656. doi:10.1038/oby.2008.607
   PubMed Web of Science ®Google Scholar
• Davis JE, Gabler NK, Walker-Daniels J, Spurlock ME. The c-Jun N-terminal kinase mediates the induction of oxidative stress and insulin resistance by palmitate and toll-like receptor 2 and 4 ligands in 3T3-L1 adipocytes. Horm Metab Res. 2009;41(7):523–530. doi:10.1055/s-0029-1202852
   PubMed Web of Science ®Google Scholar
• Kopp A, Gross P, Falk W, et al. Fatty acids as metabolic mediators in innate immunity. Eur J Clin Invest. 2009;39(10):924–933. doi:10.1111/j.1365-2362.2009.02185.x
   PubMed Web of Science ®Google Scholar
• Poulain-Godefroy O, Le Bacquer O, Plancq P, et al. Inflammatory role of Toll-like receptors in human and murine adipose tissue. Mediators Inflamm. 2010;2010:823486. doi:10.1155/2010/823486
   PubMed Web of Science ®Google Scholar
• Lee JY, Zhao L, Youn HS, et al. Saturated fatty acid activates but polyunsaturated fatty acid inhibits Toll-like receptor 2 dimerized with Toll-like receptor 6 or 1. J Biol Chem. 2004;279(17):16971–16979. doi:10.1074/jbc.M312990200
   PubMed Web of Science ®Google Scholar
• Holland WL, Bikman BT, Wang LP, et al. Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice. J Clin Invest. 2011;121(5):1858–1870. doi:10.1172/JCI43378
   PubMed Web of Science ®Google Scholar
• Uchimura K, Hayata M, Mizumoto T, et al. The serine protease prostasin regulates hepatic insulin sensitivity by modulating TLR4 signalling. Nat Commun. 2014;5(1):3428. doi:10.1038/ncomms4428
   PubMedGoogle Scholar
• Underhill DM. Toll-like receptors: networking for success. Eur J Immunol. 2003;33(7):1767–1775. doi:10.1002/eji.200324037
   PubMed Web of Science ®Google Scholar
• Lin Y, Lee H, Berg AH, Lisanti MP, Shapiro L, Scherer PE. The lipopolysaccharide-activated toll-like receptor (TLR)-4 induces synthesis of the closely related receptor TLR-2 in adipocytes. J Biol Chem. 2000;275(32):24255–24263. doi:10.1074/jbc.M002137200
   PubMed Web of Science ®Google Scholar
• Kim F, Pham M, Luttrell I, et al. Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity. Circ Res. 2007;100(11):1589–1596. doi:10.1161/CIRCRESAHA.106.142851
   PubMed Web of Science ®Google Scholar
• Poggi M, Bastelica D, Gual P, et al. C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet. Diabetologia. 2007;50(6):1267–1276. doi:10.1007/s00125-007-0654-8
   PubMed Web of Science ®Google Scholar
• Suganami T, Mieda T, Itoh M, Shimoda Y, Kamei Y, Ogawa Y. Attenuation of obesity-induced adipose tissue inflammation in C3H/HeJ mice carrying a Toll-like receptor 4 mutation. Biochem Biophys Res Commun. 2007;354(1):45–49. doi:10.1016/j.bbrc.2006.12.190
   PubMed Web of Science ®Google Scholar
• Tsukumo DM, Carvalho-Filho MA, Carvalheira JB, et al. Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance. Diabetes. 2007;56(8):1986–1998. doi:10.2337/db06-1595
   PubMed Web of Science ®Google Scholar
• Li L, Chen L, Hu L, et al. Nuclear factor high-mobility group box 1 mediating the activation of Toll-like receptor 4 signaling in hepatocytes in the early stage of nonalcoholic fatty liver disease in mice. Hepatology. 2011;54(5):1620–1630. doi:10.1002/hep.24552
   PubMed Web of Science ®Google Scholar
• Lassenius MI, Pietilainen KH, Kaartinen K, et al. Bacterial endotoxin activity in human serum is associated with dyslipidemia, insulin resistance, obesity, and chronic inflammation. Diabetes Care. 2011;34(8):1809–1815. doi:10.2337/dc10-2197
   PubMed Web of Science ®Google Scholar
• Jayashree B, Bibin YS, Prabhu D, et al. Increased circulatory levels of lipopolysaccharide (LPS) and zonulin signify novel biomarkers of proinflammation in patients with type 2 diabetes. Mol Cell Biochem. 2014;388(1–2):203–210. doi:10.1007/s11010-013-1911-4
   PubMed Web of Science ®Google Scholar
• Velloso LA, Folli F, Saad MJ. TLR4 at the crossroads of nutrients, gut microbiota, and metabolic inflammation. Endocr Rev. 2015;36(3):245–271. doi:10.1210/er.2014-1100
   PubMed Web of Science ®Google Scholar
• Hashani M, Witzel HR, Pawella LM, et al. Widespread expression of perilipin 5 in normal human tissues and in diseases is restricted to distinct lipid droplet subpopulations. Cell Tissue Res. 2018;374(1):121–136. doi:10.1007/s00441-018-2845-7
   PubMed Web of Science ®Google Scholar
• Kimmel AR, Sztalryd C. Perilipin 5, a lipid droplet protein adapted to mitochondrial energy utilization. Curr Opin Lipidol. 2014;25(2):110–117. doi:10.1097/MOL.0000000000000057
   PubMed Web of Science ®Google Scholar
• Kahn DE, Bergman BC. Keeping it local in metabolic disease: adipose tissue paracrine signaling and insulin resistance. Diabetes. 2022;71(4):599–609. doi:10.2337/dbi21-0020
   PubMed Web of Science ®Google Scholar
• Jin ES, Szuszkiewicz-Garcia M, Browning JD, Baxter JD, Abate N, Malloy CR. Influence of liver triglycerides on suppression of glucose production by insulin in men. J Clin Endocrinol Metab. 2015;100(1):235–243. doi:10.1210/jc.2014-2404
   PubMed Web of Science ®Google Scholar