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Angiotensin‐converting enzyme 2 inhibits endoplasmic reticulum stress–associated pathway to preserve nonalcoholic fatty liver disease
Author(s) -
Cao Xi,
Song LiNi,
Zhang YiChen,
Li Qi,
Shi TingTing,
Yang FangYuan,
Yuan MingXia,
Xin Zhong,
Yang JinKui
Publication year - 2019
Publication title -
diabetes/metabolism research and reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.307
H-Index - 110
eISSN - 1520-7560
pISSN - 1520-7552
DOI - 10.1002/dmrr.3123
Subject(s) - endocrinology , unfolded protein response , medicine , nonalcoholic fatty liver disease , endoplasmic reticulum , steatosis , angiotensin converting enzyme 2 , chemistry , fatty liver , protein kinase b , lipid metabolism , fatty acid synthase , insulin resistance , biology , insulin , signal transduction , biochemistry , disease , covid-19 , infectious disease (medical specialty)
Background Previous works indicated that the stress on the endoplasmic reticulum (ER) affected nonalcoholic fatty liver disease (NAFLD). However, there is no clear evident on the effect of the regulation of ER stress by angiotensin‐converting enzyme 2 (ACE2) on the prevention of NAFLD. Methods HepG2 cells were treated with thapsigargin (Tg) or palmitic acid (PA). We analysed ACE2 expression using Western‐blotting analyses. ER stress–related proteins were detected in ACE2 knockout mice and Ad‐ACE2‐treated db/db mice by immunofluorescence or Western‐blotting analyses. In ACE2‐overexpression HepG2 cells, the triglyceride (TG), total cholesterol (TC), and glycogen content were detected by assay kits. Meanwhile, the expression of hepatic lipogenic proteins (ACCα, SREBP‐1c, FAS, and LXRα), enzymes for gluconeogenesis (PEPCK, G6Pase, and IRS2), and IKKβ/NFκB/IRS1/Akt pathway were analysed by Western‐blotting analyses. Results ACE2 was significantly increased in Tg/PA‐induced cultured hepatocytes. Additionally, ACE2 knockout mice displayed elevated levels of ER stress, while Ad‐ACE2‐treated db/db mice showed reduced ER stress in liver. Furthermore, activation of ACE2 can ameliorate ER stress, accompanied by decreased TG content, increased intracellular glycogen, and downregulated expression of hepatic lipogenic proteins and enzymes for gluconeogenesis in Tg/PA‐induced hepatocytes. As a consequence of anti‐ER stress, the activation of ACE2 led to improved glucose and lipid metabolism through the IKKβ/NFκB/IRS1/Akt pathway. Conclusions This is the first time documented that ACE2 had a notable alleviating role in ER stress–induced hepatic steatosis and glucose metabolism via the IKKβ/NFκB/IRS1/Akt‐mediated pathway. This study may further provide insight into a novel underlying mechanism and a strategy for treating NAFLD.