title: An engineered FGF21 variant, LY2405319, can prevent non-alcoholic steatohepatitis by enhancing hepatic mitochondrial function.
abstract: Non-alcoholic fatty liver disease (NAFLD) is a prevalent obesity-related disease that affects large populations throughout the world due to excessive calorie intake and an increasingly sedentary lifestyle. Fibroblast growth factor 21 (FGF21) has recently emerged as a promising therapeutic candidate for the treatment of obesity and diabetes. FGF21 is a starvation-induced pleiotropic hormone with various beneficial metabolic effects, and pharmacological treatment in rodents has been shown to improve insulin sensitivity and decrease simple fatty liver disease. However, its effects on reversing the symptoms of advanced liver disease have yet to be validated. Here, we investigated the protective effects of the LY2405319 compound, an engineered FGF21 variant, in a non-alcoholic steatohepatitis (NASH) model usingleptin-deficientob/obmice and a methionine- and choline-deficient (MCD) diet to induce steatohepatitis. LY2405319 treatment inob/obmice corroborated previous results showing that improvements in the metabolic parameters were due to increased mitochondrial oxygen consumption rate and fatty acid oxidation. LY2405319 treatment inob/obmice on an MCD diet significantly reduced the symptoms of steatohepatitis, as confirmed by Masson's trichrome staining intensity. Serum levels of AST and ALT were also reduced, suggesting an attenuation of liver injury, while detection of inflammatory markers showed decreased mRNA expression of TGF-β1 and type-I collagen, and decreased phosphorylation of NF-kB p65, JNK1/2, and p38. Collectively, these data show that LY2405319 treatment attenuated MCD diet-induced NASH progression. We propose that the LY2405319 compound is a potential therapeutic candidate for the treatment of advanced liver disease.
authors.affiliation: Department of Internal Medicine, Chungnam National University HospitalDaejeon 35015, Republic of Korea; Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of MedicineDaejeon 35015, Republic of Korea.
authors.forename: Ju Hee
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine Daejeon 35015, Republic of Korea.
authors.forename: Yea Eun
authors.initials: YE
authors.lastname: Kang
authors.affiliation: Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of MedicineDaejeon 35015, Republic of Korea; Department of Medical Science, Chungnam National University School of MedicineDaejeon 35015, Republic of Korea.
authors.forename: Joon Young
authors.initials: JY
authors.lastname: Chang
authors.affiliation: Clinical Research Institute, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea Daejeon 34943, Republic of Korea.
authors.forename: Ki Cheol
authors.initials: KC
authors.lastname: Park
authors.affiliation: Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of MedicineDaejeon 35015, Republic of Korea; Department of Medical Science, Chungnam National University School of MedicineDaejeon 35015, Republic of Korea.
authors.forename: Hyeon-Woo
authors.initials: HW
authors.lastname: Kim
authors.affiliation: Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of MedicineDaejeon 35015, Republic of Korea; Department of Medical Science, Chungnam National University School of MedicineDaejeon 35015, Republic of Korea.
authors.forename: Jung Tae
authors.initials: JT
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Chungnam National University HospitalDaejeon 35015, Republic of Korea; Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of MedicineDaejeon 35015, Republic of Korea.
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine Daejeon 35015, Republic of Korea.
authors.forename: Hyon-Seung
authors.initials: HS
authors.lastname: Yi
authors.affiliation: Department of Internal Medicine, Chungnam National University HospitalDaejeon 35015, Republic of Korea; Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of MedicineDaejeon 35015, Republic of Korea.
authors.forename: Minho
authors.initials: M
authors.lastname: Shong
authors.affiliation: Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine Daejeon 35015, Republic of Korea.
authors.forename: Hyo Kyun
authors.initials: HK
authors.lastname: Chung
authors.affiliation: Department of Internal Medicine, Chungnam National University HospitalDaejeon 35015, Republic of Korea; Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of MedicineDaejeon 35015, Republic of Korea.
authors.forename: Koon Soon
authors.initials: KS
authors.lastname: Kim
keywords: FGF21; LY2405319; inflammation; mitochondria; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis