title: Association between betatrophin/ANGPTL8 and non-alcoholic fatty liver disease: animal and human studies.
abstract: Betatrophin/angiopoietin-like protein 8 (ANGPTL8) is a liver-secreted protein recently identified as a potent stimulator of beta cell proliferation in mice. However, it is unclear how betatrophin is regulated in humans with non-alcoholic fatty liver disease (NAFLD). We investigated the role of betatrophin in mice and in humans with and without NAFLD. Serum betatrophin levels were examined by ELISA in 164 subjects, including 96 patients with NAFLD. Levels were significantly elevated in subjects with NAFLD compared with controls (1.301 ± 0.617 vs. 0.900 ± 0.574 μg/L, P < 0.001), even after stratification by diabetic or obesity status. Circulating betatrophin positively correlated with obesity or glycemic indices, liver enzyme profiles, and NAFLD status, and was confirmed by multivariate regression analyses (β = 0.195, P = 0.040). However, when including insulin resistance index in the model, the significant association between betatrophin level and NAFLD was diminished due to a mediation effect of insulin resistance on this relationship. Palmitate or tunicamycin increased betatrophin expression in HepG2 cells, while a chemical chaperone blocked its induction. Hepatic expression of betatrophin was elevated in mice with NAFLD including db/db or ob/ob mice and mice with a high-fat or methionine-choline deficient diet. In conclusion, circulating betatrophin was increased in mice and humans with NAFLD and its expression was induced by endoplasmic reticulum stress in hepatocytes (Clinical trial no. NCT02285218).
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Yong-Ho
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Sang-Guk
authors.initials: SG
authors.lastname: Lee
authors.affiliation: Division of Cardiology, Severance Cardiovascular Hospital and Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Chan Joo
authors.initials: CJ
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Soo Hyun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Young-Mi
authors.initials: YM
authors.lastname: Song
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Mi Ra
authors.initials: MR
authors.lastname: Yoon
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Byung Hun
authors.initials: BH
authors.lastname: Jeon
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, Seonam University College of Medicine, Goyang-si, Gyeonggi-do, Republic of Korea.
authors.forename: Jae Hyuk
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Byung-Wan
authors.initials: BW
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Eun Seok
authors.initials: ES
authors.lastname: Kang
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyun Chul
authors.initials: HC
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Bong-Soo
authors.initials: BS
authors.lastname: Cha
mesh_terms: D000091306:Angiopoietin-Like Protein 8; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000097:blood*; D000818:Animals; D015992:Body Mass Index; D016022:Case-Control Studies; D049109:Cell Proliferation; D015897:Comorbidity; D048909:Diabetes Complications / Q000097:blood / Q000175:diagnosis; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood*; D009765:Obesity / Q000097:blood / Q000150:complications; D010168:Palmitates / Q000737:chemistry; D036361:Peptide Hormones / Q000097:blood*; D011446:Prospective Studies; D060888:Real-Time Polymerase Chain Reaction; D014415:Tunicamycin / Q000737:chemistry
chemical_list: C576683:ANGPTL8 protein, human; C000595899:ANGPTL8 protein, mouse; D000091306:Angiopoietin-Like Protein 8; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D010168:Palmitates; D036361:Peptide Hormones; D014415:Tunicamycin