Leukemia inhibitory factor protects against liver steatosis in nonalcoholic fatty liver disease patients and obese mice

Abstract

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. However, the molecular mechanisms that promote dysregulation of hepatic triglyceride metabolism and lead to NAFLD are poorly understood, and effective treatments are limited. Leukemia inhibitory factor (LIF) is a member of the interleukin-6 cytokine family and has been shown to regulate a variety of physiological processes, although its role in hepatic triglyceride metabolism remains unknown. In the present study, we measured circulating LIF levels by ELISA in 214 patients with biopsy-diagnosed NAFLD as well as 314 normal control patients. We further investigated the potential role and mechanism of LIF on hepatic lipid metabolism in obese mice. We found that circulating LIF levels correlated with the severity of liver steatosis. Patients with ballooning, fibrosis, lobular inflammation, and abnormally elevated liver injury markers alanine transaminase and aspartate aminotransferase also had higher levels of serum LIF than control patients. Furthermore, animal studies showed that white adipose tissue–derived LIF could ameliorate liver steatosis through activation of hepatic LIF receptor signaling pathways. Together, our results suggested that targeting LIF-LIF receptor signaling might be a promising strategy for treating NAFLD. Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. However, the molecular mechanisms that promote dysregulation of hepatic triglyceride metabolism and lead to NAFLD are poorly understood, and effective treatments are limited. Leukemia inhibitory factor (LIF) is a member of the interleukin-6 cytokine family and has been shown to regulate a variety of physiological processes, although its role in hepatic triglyceride metabolism remains unknown. In the present study, we measured circulating LIF levels by ELISA in 214 patients with biopsy-diagnosed NAFLD as well as 314 normal control patients. We further investigated the potential role and mechanism of LIF on hepatic lipid metabolism in obese mice. We found that circulating LIF levels correlated with the severity of liver steatosis. Patients with ballooning, fibrosis, lobular inflammation, and abnormally elevated liver injury markers alanine transaminase and aspartate aminotransferase also had higher levels of serum LIF than control patients. Furthermore, animal studies showed that white adipose tissue–derived LIF could ameliorate liver steatosis through activation of hepatic LIF receptor signaling pathways. Together, our results suggested that targeting LIF-LIF receptor signaling might be a promising strategy for treating NAFLD. Nonalcoholic fatty liver disease (NAFLD) has become one of the most common chronic liver diseases worldwide (1Younossi Z. Anstee Q.M. Marietti M. Hardy T. Henry L. Eslam M. George J. Bugianesi E. Global burden of NAFLD and NASH: Trends, predictions, risk factors and prevention.Nat. Rev. Gastroenterol. Hepatol. 2018; 15: 11-20Crossref PubMed Scopus (2033) Google Scholar), causing a heavy burden to society. It is characterized by accumulation of excessive triglycerides (TGs) in the hepatocytes and closely related to insulin resistance and cardiometabolic risk factors (i.e., abdominal obesity, dyslipidemia, and hyperglycemia) (2Younossi Z.M. Koenig A.B. 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: 73-84Crossref PubMed Scopus (4622) Google Scholar, 3Khan R.S. Bril F. Cusi K. Newsome P.N. Modulation of insulin resistance in nonalcoholic fatty liver disease.Hepatol. (Baltimore, Md.). 2019; 70: 711-724PubMed Google Scholar, 4Cai J. Zhang X.J. Ji Y.X. Zhang P. She Z.G. Li H. Nonalcoholic fatty liver disease pandemic fuels the upsurge in cardiovascular diseases.Circ. Res. 2020; 126: 679-704Crossref PubMed Scopus (58) Google Scholar, 5Younossi Z. Tacke F. Arrese M. Chander Sharma B. Mostafa I. Bugianesi E. Wai-Sun Wong V. Yilmaz Y. George J. Fan J. Vos M.B. Global perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.Hepatol. (Baltimore, Md.). 2019; 69: 2672-2682Crossref PubMed Scopus (608) Google Scholar). NAFLD can further develop into nonalcoholic steatohepatitis (NASH) characterized by persistent liver injury and inflammation, which can progress to hepatic fibrosis, liver cirrhosis, and hepatocellular carcinoma (1Younossi Z. Anstee Q.M. Marietti M. Hardy T. Henry L. Eslam M. George J. Bugianesi E. Global burden of NAFLD and NASH: Trends, predictions, risk factors and prevention.Nat. Rev. Gastroenterol. Hepatol. 2018; 15: 11-20Crossref PubMed Scopus (2033) Google Scholar, 6Francque S. Szabo G. Abdelmalek M.F. Byrne C.D. Cusi K. Dufour J.F. Roden M. Sacks F. Tacke F. Nonalcoholic steatohepatitis: The role of peroxisome proliferator-activated receptors.Nat. Rev. Gastroenterol.Hepatol. 2020; 18: 24-39Crossref PubMed Scopus (71) Google Scholar, 7Rotman Y. Sanyal A.J. Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease.Gut. 2017; 66: 180-190Crossref PubMed Scopus (268) Google Scholar). However, the molecular mechanisms of NAFLD remain to be further determined. Furthermore, it is important to seek new potential therapeutic targets. Leukemia inhibitory factor (LIF) is a member of the interleukin (IL)-6 cytokine family, which plays important roles in the regulation of many different physiological and pathological processes. It induces activation of signal transducer and activator of transcription (STAT) and mitogen-activated protein kinase (MAPK) pathways by binding to its receptor—LIF receptor (LIFR) (8Zhang C. Liu J. Wang J. Hu W. Feng Z. The Emerging Role of Leukemia Inhibitory Factor in Cancer and Therapy.Pharmacol. Ther. 2020; 221: 107754Crossref PubMed Scopus (13) Google Scholar). Notably, previous studies have shown that LIF can regulate the self-renewal of embryonic stem cells and the tumorigenesis (9Nicola N.A. Babon J.J. Leukemia inhibitory factor (LIF).Cytokine Growth Factor Rev. 2015; 26: 533-544Crossref PubMed Scopus (220) Google Scholar, 10Dahéron L. Opitz S.L. Zaehres H. Lensch M.W. Andrews P.W. Itskovitz-Eldor J. Daley G.Q. LIF/STAT3 signaling fails to maintain self-renewal of human embryonic stem cells.Stem Cells (Dayton, Ohio). 2004; 22: 770-778Crossref PubMed Scopus (375) Google Scholar). For instance, LIF secreted from pancreatic stellate cells acts on cancer cells to regulate cancer cell differentiation, and changes in the circulating LIF levels are significantly correlated with tumor response to therapy (11Shi Y. Gao W. Lytle N.K. Huang P. Yuan X. Dann A.M. Ridinger-Saison M. DelGiorno K.E. Antal C.E. Liang G. Atkins A.R. Erikson G. Sun H. Meisenhelder J. Terenziani E. et al.Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring.Nature. 2019; 569: 131-135Crossref PubMed Scopus (158) Google Scholar). In addition, recent studies suggest that LIF might be involved in metabolic regulation (12Jansson J.O. Movérare-Skrtic S. Berndtsson A. Wernstedt I. Carlsten H. Ohlsson C. Leukemia inhibitory factor reduces body fat mass in ovariectomized mice.Eur. J. Endocrinol. 2006; 154: 349-354Crossref PubMed Scopus (17) Google Scholar, 13Beretta E. Dhillon H. Kalra P.S. Kalra S.P. Central LIF gene therapy suppresses food intake, body weight, serum leptin and insulin for extended periods.Peptides. 2002; 23: 975-984Crossref PubMed Scopus (47) Google Scholar, 14Brandt N. O'Neill H.M. Kleinert M. Schjerling P. Vernet E. Steinberg G.R. Richter E.A. Jørgensen S.B. Leukemia inhibitory factor increases glucose uptake in mouse skeletal muscle.Am. J. Physiol. Endocrinol. Metab. 2015; 309: E142-E153Crossref PubMed Scopus (24) Google Scholar, 15Arora G.K. Gupta A. Narayanan S. Guo T. Iyengar P. Infante R.E. Cachexia-associated adipose loss induced by tumor-secreted leukemia inhibitory factor is counterbalanced by decreased leptin.JCI Insight. 2018; 3e121221Crossref Scopus (35) Google Scholar). It has been shown that central LIF gene therapy suppresses food intake and decreases body weight and serum leptin in animal models (13Beretta E. Dhillon H. Kalra P.S. Kalra S.P. Central LIF gene therapy suppresses food intake, body weight, serum leptin and insulin for extended periods.Peptides. 2002; 23: 975-984Crossref PubMed Scopus (47) Google Scholar). Florholmen et al. reported that LIF stimulates glucose transport in isolated cardiomyocytes (16Florholmen G. Thoresen G.H. Rustan A.C. Jensen J. Christensen G. Aas V. Leukaemia inhibitory factor stimulates glucose transport in isolated cardiomyocytes and induces insulin resistance after chronic exposure.Diabetologia. 2006; 49: 724-731Crossref PubMed Scopus (18) Google Scholar). Besides, Edwin et al. found that LIF could induce human β-cell differentiation in response to increased metabolic demands (17Rosado-Olivieri E.A. Aigha II, Kenty J.H. Melton D.A. Identification of a LIF-responsive, replication-competent subpopulation of human β cells.Cell Metab. 2020; 31: 327-338.e6Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar). However, its role in the regulation of hepatic TG homeostasis has not been In the present study, through human studies and animal we found that serum LIF levels significantly with severity of NAFLD and LIF could fatty liver through binding to and the signaling our results a potential therapeutic for the of fatty liver and related metabolic the potential of LIF on metabolism has been N. O'Neill H.M. Kleinert M. Schjerling P. Vernet E. Steinberg G.R. Richter E.A. Jørgensen S.B. Leukemia inhibitory factor increases glucose uptake in mouse skeletal muscle.Am. J. Physiol. Endocrinol. Metab. 2015; 309: E142-E153Crossref PubMed Scopus (24) Google Scholar, M. B. J. C. N. C.D. of leukemia inhibitory factor 2017; PubMed Scopus Google Scholar), its role in hepatic lipid metabolism is unknown. we the serum LIF levels and NAFLD. of human 314 normal and 214 NAFLD in the The and of are in patients with NAFLD had higher serum LIF levels than the and Furthermore, patients with steatosis and had higher levels of serum LIF than patients with steatosis and with and showed that patients with NAFLD had higher levels of serum LIF than with It is that serum LIF higher in obese patients than in patients with patients with normal serum alanine transaminase and aspartate aminotransferase patients with elevated and levels had higher levels of serum LIF and patients with ballooning, fibrosis, lobular had elevated serum LIF levels with Furthermore, showed that serum LIF levels with serum and homeostasis assessment of insulin resistance results that LIF might be involved in the of of patients with NAFLD and for and on on on on on on on on on alanine aspartate body mass homeostasis assessment of insulin leukemia inhibitory white are as the for and on in a new LIF levels are elevated in patients with serum LIF in normal and NAFLD serum LIF in normal and of serum LIF levels in patients with NAFLD with different serum LIF in and obese serum LIF levels in with and normal serum LIF levels in with and normal of serum LIF in with the of of serum LIF in with the of of serum LIF in with the of lobular serum LIF and and For alanine aspartate homeostasis assessment of insulin leukemia inhibitory nonalcoholic fatty nonalcoholic fatty liver NAFLD nonalcoholic of patients with NAFLD and with with on with with with with with with on with with with with with with with with on with with on with with on with with on with with on with with with with on with with on with with alanine aspartate body mass homeostasis assessment of insulin leukemia inhibitory white are as the with on in a new alanine aspartate body mass homeostasis assessment of insulin leukemia inhibitory white are as the alanine aspartate body mass homeostasis assessment of insulin leukemia inhibitory white are as the further the role of LIF in lipid metabolism and fatty the of LIF in by showed that LIF in white adipose and a in white adipose In its in the adipose skeletal and than in LIF in the and protein levels of LIF in the adipose of a for with a normal the and protein and levels of LIF significantly increased in the and of mice. LIF in adipose increased in with Furthermore, serum LIF significantly elevated in and and showed that protein levels of LIF in correlated with circulating LIF and In isolated and from of of LIF In isolated the of LIF higher in than in and In the LIF levels significantly elevated in adipose and adipose of obese and elevated serum LIF levels be to its increased in in further increased LIF in could the of fatty LIF gene into on of obese to the of circulating LIF levels of obese mice. shown in the of LIF in of not in metabolic a in circulating LIF in body weight the the mass of significantly decreased in and Furthermore, that the in significantly in the to the metabolic and in the adipose with the and as and significantly decreased in the of The fatty β and also decreased in to in the control the of and not significantly results suggest that LIF mass and and S. M. G. A. N. M. S. A. E. M. et changes of the adipose to with increased demands of PubMed Scopus Google Scholar). in adipose has been well to promote insulin resistance in H. L. control of adipose 2019; Full Text Full Text PDF PubMed Scopus Google Scholar). and insulin that of LIF glucose and insulin and is as the of in cell lipid to fatty and as for and with insulin and T. Liu Li Y. Li H. L. X. S. J. Li Huang Y. Zhang J. Zhang Z. J. Huang C. et by adipose Scopus Google Scholar, M. Wang Y. in J. PubMed Scopus Google Scholar). The of a for in significantly decreased in the and Furthermore, the serum fatty results suggest that might not be the factor that the of In addition, serum TG and levels also significantly in and of LIF in adipose from NAFLD. a for with LIF through into and in a of the strategy to of LIF levels in protein levels of LIF by ELISA in of with serum LIF levels in of mice. body weight and weight in of mice. of of levels of involved in and in insulin for the and with of glucose for the and with of protein levels of in from and mice. serum TG levels in of mice. liver weight in of mice. of liver of liver TG in of mice. of involved in lipid transport and in the of of of and pathways in the of are as protein fatty white adipose and leukemia inhibitory for nonalcoholic fatty liver normal signal transducer and activator of transcription further the the metabolism after LIF we the metabolic changes in the in liver weight the on as shown by and liver TG TG by the of and lipid uptake and C.D. G. Hepatol. 2015; Full Text Full Text PDF PubMed Scopus Google Scholar). The levels of for and decreased in the the levels of for and and lipid transport and showed Besides, levels of involved in and of LIF significantly and and in the liver a of for the fat H. L. and in nonalcoholic fatty liver Rev. Gastroenterol. Hepatol. 18: PubMed Scopus Google Scholar). further the mechanism of LIF in the regulation of LIF gene into on in mice. of LIF in the of The circulating LIF significantly increased in the in body weight the The LIF not in with the in liver weight the showed hepatic steatosis in and liver TG hepatic significantly in the further the potential mechanism of signaling pathways by LIF in activation of signaling in the of with as shown by the protein kinase for and kinase signaling pathways of LIF the signaling in the results that of LIF in could ameliorate liver steatosis by the signaling the in the of LIF protein on TG accumulation in cells and mouse hepatocytes The of LIF on the in cells insulin which In LIF protein significantly TG induced by insulin in and and The levels of gene by LIF and the related involved in lipid and not LIF in activation of signaling as shown by the and signaling pathways and studies have that the of is in through of a transcription factor in the control of and TG K. T. Central role of of cytokine signaling in hepatic insulin and the metabolic in the S. A. 2004; PubMed Scopus Google Scholar). The levels of also in cells with LIF and in the of and activation for the of a to significantly activation of in showed that the of LIF on TG and gene and Furthermore, LIF showed on lipid and LIF through which is the receptor for in of significantly the of and the of TG levels by LIF protein after LIF and significantly after In addition, on lipid transport and suggest that LIF could the by binding to the The role of hepatic in lipid metabolism further The and protein levels of significantly in the of with that in the and the of hepatic a of its in and obese also In the and protein levels of decreased in the of and with Furthermore, also and protein levels in the liver of and The hepatic of in human with normal the significantly in the liver of NAFLD patients suggest that the of hepatic is involved in the of is in obese mice. and levels and protein levels of in the of and and levels and protein levels of in the of and and levels and protein levels of in the of for and levels and protein levels of in the of for of in human normal and NAFLD liver are as leukemia inhibitory factor normal of LIF hepatic lipid accumulation in obese hepatic had with control shown in and of in of not in metabolic weight and liver weight not the and to on as shown by Furthermore, decreased hepatic TG accumulation levels also significantly in insulin the and and a in insulin resistance and glucose in and of in the of significantly the as well as on and lipid transport In with the of levels of significantly in with the results in the with also significantly liver and serum TG of significantly insulin and the of involved in and the significantly after of and Together, results that hepatic of could liver steatosis. The of NAFLD is the the of and the of that the of is to excessive in the is is abnormally secreted M. J. E. X. M. for the of nonalcoholic 2020; Full Text Full Text PDF PubMed Scopus Google Scholar, Z. Y. J. Li H. Emerging molecular for of nonalcoholic fatty liver Endocrinol. Metab. 2019; Full Text Full Text PDF PubMed Scopus Google Scholar). and response protein are the transcription factors in the and is the factor which involved in TG R.S. Bril F. Cusi K. Newsome P.N. Modulation of insulin resistance in nonalcoholic fatty liver disease.Hepatol. (Baltimore, Md.). 2019; 70: 711-724PubMed Google Scholar). Besides, the of can be by signaling signaling K. T. Central role of of cytokine signaling in hepatic insulin and the metabolic in the S. A. 2004; PubMed Scopus Google Scholar, H. W. M. S. M. K. N. Y. T. H. K. S. H. D. et of in regulation of hepatic and metabolism in 2004; PubMed Scopus Google Scholar). in obese the is and is in the liver K. T. Central role of of cytokine signaling in hepatic insulin and the metabolic in the S. A. 2004; PubMed Scopus Google Scholar). In the present study, we LIF as a white secreted protein that hepatic steatosis through activation of hepatic the levels of LIF in and serum increased in obese models and patients with NAFLD. Furthermore, circulating LIF levels significantly and correlated with metabolic risk of LIF in and insulin resistance in obese mice. LIF through the signaling which in TG accumulation in the our results that LIF might NAFLD. studies have shown that LIF many (9Nicola N.A. Babon J.J. Leukemia inhibitory factor (LIF).Cytokine Growth Factor Rev. 2015; 26: 533-544Crossref PubMed Scopus (220) Google Scholar, 10Dahéron L. Opitz S.L. Zaehres H. Lensch M.W. Andrews P.W. Itskovitz-Eldor J. Daley G.Q. LIF/STAT3 signaling fails to maintain self-renewal of human embryonic stem cells.Stem Cells (Dayton, Ohio). 2004; 22: 770-778Crossref PubMed Scopus (375) Google Scholar, E.A. Aigha II, Kenty J.H. Melton D.A. Identification of a LIF-responsive, replication-competent subpopulation of human β cells.Cell Metab. 2020; 31: 327-338.e6Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, E. The role of the leukemia inhibitory factor (LIF) in and of stem PubMed Scopus Google Scholar). It has been that LIF in tumor and circulating LIF levels significantly increased in patients with pancreatic cancer and carcinoma (11Shi Y. Gao W. Lytle N.K. Huang P. Yuan X. Dann A.M. Ridinger-Saison M. DelGiorno K.E. Antal C.E. Liang G. Atkins A.R. Erikson G. Sun H. Meisenhelder J. Terenziani E. et al.Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring.Nature. 2019; 569: 131-135Crossref PubMed Scopus (158) Google Scholar, C. Liang Y. Leukemia inhibitory factor carcinoma and PubMed Scopus Google Scholar). LIF also as a tumor-secreted that adipose and body weight loss in G.K. Gupta A. Narayanan S. Guo T. Iyengar P. Infante R.E. Cachexia-associated adipose loss induced by tumor-secreted leukemia inhibitory factor is counterbalanced by decreased leptin.JCI Insight. 2018; 3e121221Crossref Scopus (35) Google Scholar). our studies showed that increased and circulating LIF levels with the obese We found that the of LIF in significantly and protein and serum LIF also significantly increased in and mice. In we that circulating LIF significantly increased in with NAFLD and significantly with severity of NAFLD and metabolic risk our that of circulating LIF levels in and of the in different Besides, we that LIF levels correlated with the results suggest that changes in LIF levels in the of NAFLD. studies are to the of LIF in the In addition, we found that the of LIF in human Notably, levels in obese elevated circulating LIF fatty liver and insulin resistance in and in that LIF is in we LIF into of mice. the of circulating LIF levels in the disease we a of a LIF in adipose inflammation, in insulin elevated serum and hepatic steatosis. hepatic LIF not in the results suggested that the of liver metabolic homeostasis be to the elevated serum LIF levels after of LIF in Furthermore, LIF protein TG accumulation and gene induced by results suggested that LIF might metabolic LIF to cells through which is of a signal by with cytokine family and cytokine factor S. of Rev. PubMed Scopus Google Scholar). has in the of and it plays a role in the and of cancer S. of Rev. PubMed Scopus Google Scholar). signal is important family and metabolic that significantly in the of obese and patients with NAFLD. in obese the signaling fatty liver and insulin and the of hepatic of in cells the on lipid accumulation of our that signal a role in the NAFLD. In addition, our showed that levels of LIF in and serum elevated in obese and obese In hepatic of in NAFLD our suggested that of in the liver to elevated circulating LIF levels in serum LIF levels in be to a response to in the which is to as reported A. E. is a factor PubMed Scopus Google Scholar, H. Gao F. Fan J. J. Wang X. Zhang H. X. Y. K. A. W. factor levels are increased in nonalcoholic fatty liver disease patients and are correlated with hepatic Hepatol. Full Text Full Text PDF PubMed Scopus Google Scholar, J. V. P. M. G. F. in and levels and of the receptor for in obese J. Scopus Google Scholar). studies showed that serum levels elevated in patients with NAFLD and obese of the of in liver and A. E. is a factor PubMed Scopus Google Scholar, H. Gao F. Fan J. J. Wang X. Zhang H. X. Y. K. A. W. factor levels are increased in nonalcoholic fatty liver disease patients and are correlated with hepatic Hepatol. Full Text Full Text PDF PubMed Scopus Google Scholar, J. V. P. M. G. F. in and levels and of the receptor for in obese J. Scopus Google metabolic and induces weight loss in obese A. E. is a factor PubMed Scopus Google Scholar). suggested that NAFLD be a of in that hepatic Furthermore, our results showed that LIF in and protein levels of LIF correlated with circulating LIF in animal results that might be important of However, we the that LIF from might also be involved in the regulation of hepatic lipid It has been reported that glucose M. B. J. C. N. C.D. of leukemia inhibitory factor 2017; PubMed Scopus Google Scholar), LIF protein increased glucose uptake N. O'Neill H.M. Kleinert M. Schjerling P. Vernet E. Steinberg G.R. Richter E.A. Jørgensen S.B. Leukemia inhibitory factor increases glucose uptake in mouse skeletal muscle.Am. J. Physiol. Endocrinol. Metab. 2015; 309: E142-E153Crossref PubMed Scopus (24) Google Scholar). In our suggested that glucose and insulin in and in of to the role and mechanism of in the of glucose the it is that can many signaling and pathways H. T. I. A. of embryonic stem cells is activation of PubMed Scopus Google Scholar, X. H. L. Y. Zhang C. X. Liu Z. H. Feng Z. Hu W. LIF tumorigenesis and of cancer through the PubMed Scopus Google Scholar). showed that the signaling to and related to TG to TG in the liver of obese mice. However, our that LIF had on the signaling pathways in the of LIF and signaling pathways by LIF might be in different and disease our showed that LIF could the metabolic further studies are to the and potential of LIF in NAFLD to its (11Shi Y. Gao W. Lytle N.K. Huang P. Yuan X. Dann A.M. Ridinger-Saison M. DelGiorno K.E. Antal C.E. Liang G. Atkins A.R. Erikson G. Sun H. Meisenhelder J. Terenziani E. et al.Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring.Nature. 2019; 569: 131-135Crossref PubMed Scopus (158) Google Scholar, 15Arora G.K. Gupta A. Narayanan S. Guo T. Iyengar P. Infante R.E. Cachexia-associated adipose loss induced by tumor-secreted leukemia inhibitory factor is counterbalanced by decreased leptin.JCI Insight. 2018; 3e121221Crossref Scopus (35) Google Scholar, C. Liang Y. Leukemia inhibitory factor carcinoma and PubMed Scopus Google Scholar). the activation of might be therapeutic for the of NAFLD. has in study, we LIF into of to promote the of LIF of adipose mice. However, we LIF in which in increased circulating LIF although LIF the signaling in we could not the that LIF induces the activation of pathways. might to signaling in response to LIF the on with a further studies with to the circulating LIF and NAFLD and metabolic The present that LIF important of liver TG of hepatic to the increased circulating LIF levels in LIF hepatic steatosis and insulin resistance in a mouse of NAFLD. our a new therapeutic for NAFLD. In of the of it be to LIF as a therapeutic However, it be to into the of NAFLD new that can be to of

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