Liver Expressed Antimicrobial Peptide 2 is Associated with Steatosis in Mice and Humans

Abstract

Background and Aims Liver expressed antimicrobial peptide 2 (LEAP2) is recently identified as a regulator in energy metabolism. This study aims to 1) investigate the role of leap2 in hepatic steatosis in C57BL/6 mice; 2) evaluate the association between circulating LEAP2 levels and liver fat contents in a hospital based case-control study. Methods The rodent experiment: western blotting and qPCR were performed to evaluate leap2 levels, lipid metabolism pathways and insulin signaling. shRNA was used to knockdown leap2. The clinical study: commercial ELISA kits were used to measure circulating LEAP2 levels (validated by western blotting). Liver fat content was estimated using MRI-derived proton density fat fraction and FibroScan-derived controlled attenuation parameter. Results The rodent experiment found the hepatic expression and secreted levels of leap2 were increased in mice with diet-induced steatosis. Leap2 knockdown ameliorated steatosis via lipolytic/lipogenic pathway and improved insulin sensitivity via IRS/AKT signaling. The clinical study reported increased circulating levels of LEAP2 in the subjects with steatosis. Moreover, LEAP2 correlated positively with age, body mass index, waist-to-hip ratio, liver fat content, fasting insulin and HOMA-IR, whereas inversely with acyl-ghrelin. Furthermore, the circulating levels of LEAP2 are dependent on liver fat content, acyl-ghrelin and fasting glucose. Lastly, circulating LEAP2 is an independent predictor of NAFLD. Conclusions The study suggests LEAP2 is associated with hepatic steatosis, which may involve lipolytic/lipogenic pathway and insulin signaling.

LEAP2 deletion in mice enhances ghrelin's actions as an orexigen and growth hormone secretagogue

“…demonstrated increased circulating LEAP2 and reported increased hepatic LEAP2 content in high-fat diet-fed C57BL/6J mice as compared to standard chow diet-fed mice [ 14 ]. Also, plasma LEAP2 was positively correlated with body mass index, HOMA-IR, waist-to-hip ratio, fasting insulin, age, and hepatic fat content in humans [ 14 ]. Islam et al.…”

LEAP-2: An Emerging Endogenous Ghrelin Receptor Antagonist in the Pathophysiology of Obesity

“…However, LEAP-2 levels showed no significant difference between cohorts with BMI between 25 ~ 40 and BMI < 25 ( 10 ). Indeed, LEAP-2 level positively correlated with BMI, and various other metabolic parameters of obesity, including body fat percentage, waist-to-hip ratio, blood glucose and triglycerides, visceral adipose tissue volume, liver lipid content, fasting insulin, and homeostatic model assessment for insulin resistance (HOMA-IR) ( 10 , 57 ).…”

“…In mice with diet-induced NAFLD, hepatic expression and plasma level of LEAP-2 were increased ( 57 ). Circulating LEAP-2 is also elevated in patients with NAFLD ( 57 ).…”

“…In mice with diet-induced NAFLD, hepatic expression and plasma level of LEAP-2 were increased ( 57 ). Circulating LEAP-2 is also elevated in patients with NAFLD ( 57 ). In consistent with this, an in vitro study revealed that LEAP-2 expression was induced by high-cholesterol sera treatment in a human hepatoma cell line ( 53 ).…”

“…To confirm the role LEAP-2 playing in the development of NAFLD, the authors knocked down LEAP-2 using short hairpin RNA (shRNA) in the NAFLD mouse model. The result showed that hepatic steatosis was relieved following the reduction in LEAP-2 level, which resulted from alterations in lipolytic and lipogenic gene expression as well as improved insulin sensitivity ( 57 ). The enhanced lipid catabolism may derive from the effect of GH.…”