Premium
Engineered FGF21 variant, LY2405319, can protect nonalcoholic fatty liver disease through enhancing hepatic mitochondrial function
Author(s) -
CHUNG HYO KYUN,
Kang Yea Eun,
Hwang Jin Hee,
Kim Koon Soon,
Shong Minho
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.742.10
Subject(s) - nonalcoholic fatty liver disease , medicine , steatosis , insulin resistance , endocrinology , fatty liver , hepatocyte , cirrhosis , fgf21 , liver function , fibrosis , biology , insulin , disease , biochemistry , receptor , fibroblast growth factor , in vitro
Objective Nonalcoholic fatty liver disease (NAFLD) is one of the causes of fatty liver, linked to insulin resistance, metabolic syndrome, liver fibrosis and cirrhosis. Traditionally, NAFLD has been recognized as a result of excess nutrient intake. However, the molecular target of NAFLD has not been fully addressed. The increased ROS/RNS and mitochondrial dysfunction of hepatocyte can play critical roles in the development of NAFLD and nonalcoholic fatty liver (NASH) through chronic inflammation and insulin resistance. We here show that the beneficial effects of LY2405319, an Engineered FGF21 Variant (lilly, USA), on NAFND using ob/ob mice model. Methods The 6‐week‐old male ob/+ control and ob/ob C57BL/6J Lep (−/−) mice were divided into three groups, including ob/+ control, vehicle‐treated (ob/ob‐vehicle) and LY2405319‐treated group (ob/ob‐LY). The vehicle and LY2405319 (5mg/kg) were administered oral gavage for 3 weeks. Body weight was recorded every 2 days. Intraperitoneal glucose tolerance test and energy expenditure were performed after LY2405319 treatment for 3 weeks. The effects of LY2405319 on NAFLD progression were evaluated using biochemical, hitological and molecular markers. Oxygen consumption rate (OCR) and mitochondrial gene expressions were measured to determine the effects on mitochondria in ob/ob mouse and primary hepatocyte. Results LY2405319 treated ob/ob mice revealed decreased body weight and serum glucose levels and markedly decrease of serum AST, serum ALT and hepatic triglycerides compared to control group. And also, hepatic steatosis and lipid peroxidation significantly improved compared to control group. Interestingly, LY2405319 treatment mice group showed increased energy expenditures and significantly increased in mitochondrial transcriptional‐, and translational gene expression than control group. Furthermore, LY2405319 increased OCR by dose dependent manner in primary hepatocytes. Support or Funding Information This work was supported from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, and Future Planning, Korea (NRF‐2015R1A2A1A13000951). H.K.C. and J.H.H were supported by NTF grant, the Ministry of Education (MOE), Korea (NRF‐2013R1A1A2058889).