Angiotensin-converting enzyme 2 inhibits endoplasmic reticulum stress-associated pathway to preserve non-alcoholic fatty liver disease.

BACKGROUND: Previous works indicated that the stress on the endoplasmic reticulum (ER) affected non-alcoholic fatty liver disease (NAFLD). However, there is no clear evident on the effect of the regulation of ER stress by ACE2 on the prevention of NAFLD.

METHODS: HepG2 cells were treated with Tg (thapsigargin) or PA (palmitic acid). We analyzed 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), as well as IKKβ/NFκB/IRS1/Akt pathway were analyzed 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, as well as down-regulated 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.