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).
Highlights
Non-alcoholic fatty liver disease (NAFLD) is emerging as a worldwide public health issue because the prevalence of obesity is increasing, populations are aging, and sedentary lifestyles prevail[1]
Recent human studies reported that serum betatrophin levels are increased in subjects with type 1 diabetes (T1D)[16], obesity[17], and type 2 diabetes (T2D)[17,18,19], there is no report of the role of betatrophin in patients with fatty liver
Considering that obesity, T2D, and NAFLD share insulin resistance as a common pathophysiologic mechanism[20] and that the dominant expression of betatrophin is in human liver[12], we hypothesized that circulating betatrophin levels might be elevated in subjects with NAFLD
Summary
Non-alcoholic fatty liver disease (NAFLD) is emerging as a worldwide public health issue because the prevalence of obesity is increasing, populations are aging, and sedentary lifestyles prevail[1]. NAFLD is defined histologically as the accumulation of ectopic liver fat (mainly triglycerides) in more than 5% of hepatocytes with no evidence of significant alcohol intake or other secondary etiology of liver disease. It is implicated in an increased risk of mortality[2] as well as serious comorbidities like diabetes and cardiovascular diseases[3,4,5]. Despite its high prevalence and consequences, NAFLD screening and detection primarily depends on expensive imaging devices, including ultrasonography, or blood assays of liver enzyme profiles, which are often inaccurate[8]. The present study investigates the circulating levels of betatrophin and the clinical parameters associated with betatrophin levels in subjects from a human cohort with or without NAFLD, which is further elucidated using in vivo and in vitro models
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