Abstract
The classical axis of renin-angiotensin system (RAS), angiotensin (Ang)-converting enzyme (ACE)/Ang II/AT1, contributes to the development of non-alcoholic fatty liver disease (NAFLD). However, the role of bypass axis of RAS (Angiotensin-converting enzyme 2 (ACE2)/Ang-(1–7)/Mas) in hepatic steatosis is still unclear. Here we showed that deletion of ACE2 aggravates liver steatosis, which is correlated with the increased expression of hepatic lipogenic genes and the decreased expression of fatty acid oxidation-related genes in the liver of ACE2 knockout (ACE2−/y) mice. Meanwhile, oxidative stress and inflammation were also aggravated in ACE2−/y mice. On the contrary, overexpression of ACE2 improved fatty liver in db/db mice, and the mRNA levels of fatty acid oxidation-related genes were up-regulated. In vitro, Ang-(1–7)/ACE2 ameliorated hepatic steatosis, oxidative stress and inflammation in free fatty acid (FFA)-induced HepG2 cells, and what’s more, Akt inhibitors reduced ACE2-mediated lipid metabolism. Furthermore, ACE2-mediated Akt activation could be attenuated by blockade of ATP/P2 receptor/Calmodulin (CaM) pathway. These results indicated that Ang-(1–7)/ACE2/Mas axis may reduce liver lipid accumulation partly by regulating lipid-metabolizing genes through ATP/P2 receptor/CaM signaling pathway. Our findings support the potential role of ACE2/Ang-(1–7)/Mas axis in prevention and treatment of hepatic lipid metabolism.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver disorders worldwide1
The protein levels of lipid-metabolizing genes, including sterol regulatory element-binding protein-1c (SREBP-1c), acetyl-CoA carboxylase α (ACCα ), liver X receptor-α (LXRα ), fatty acid synthase (FAS) and uncoupling protein-2 (UCP-2) were up-regulated, whereas adiponectin receptor 1 (AdipoR1) was repressed in ACE2−/y mice (Fig. 2A)
The mRNA levels of fatty acid oxidation-related genes, carnitine palmitoyltransferase Iα (CPT-1α), peroxisome proliferator-activated receptor alpha (PPARα), PPAR gamma (PPARγ) and PPARγ coactivator 1α (PGC-1α) were down-regulated, and little change was observed in medium chain acy -CoA dehydrogenas (MCAD) in the liver of ACE2−/y mice (Fig. 2B)
Summary
Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver disorders worldwide. Ang II causes development and progression of NAFLD in the transgenic Ren rat model (with elevated tissue Ang II) by increasing hepatic reactive oxygen species (ROS). Ang II causes development and progression of NAFLD in the transgenic Ren rat model (with elevated tissue Ang II) by increasing hepatic reactive oxygen species (ROS)5 Increased activation of both systemic and local RAS has been noted in the patients with cirrhosis and chronic hepatitis C7. We reported that activation of the ACE2/Ang-(1–7)/ Mas axis led to improved hepatic insulin resistance through the Akt/PI3K/IRS-1/JNK insulin signaling pathway. We provide physiological and molecular evidences for ACE2/Ang-(1–7)/Mas axis improvement in hepatic steatosis and provide new insights and understanding into possible hepatic lipid metabolism mechanisms of ACE2/Ang-(1–7)/Mas axis
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