title: Angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis activates Akt signaling to ameliorate hepatic steatosis.
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.
authors.affiliation: Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing 10730, China.|Beijing Key Laboratory of Diabetes Research and Care, Beijing 100730, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing 10730, China.|Beijing Key Laboratory of Diabetes Research and Care, Beijing 100730, China.
authors.forename: Fangyuan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing 10730, China.|Beijing Key Laboratory of Diabetes Research and Care, Beijing 100730, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Shi
authors.affiliation: Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing 10730, China.|Beijing Key Laboratory of Diabetes Research and Care, Beijing 100730, China.
authors.forename: Mingxia
authors.initials: M
authors.lastname: Yuan
authors.affiliation: Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing 10730, China.|Beijing Key Laboratory of Diabetes Research and Care, Beijing 100730, China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Xin
authors.affiliation: Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing 10730, China.|Beijing Key Laboratory of Diabetes Research and Care, Beijing 100730, China.
authors.forename: Rongrong
authors.initials: R
authors.lastname: Xie
authors.affiliation: Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing 10730, China.|Beijing Key Laboratory of Diabetes Research and Care, Beijing 100730, China.
authors.forename: Sen
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing 10730, China.|Beijing Key Laboratory of Diabetes Research and Care, Beijing 100730, China.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing 10730, China.|Beijing Key Laboratory of Diabetes Research and Care, Beijing 100730, China.
authors.forename: Jin-Kui
authors.initials: JK
authors.lastname: Yang
mesh_terms: D000803:Angiotensin I / Q000378:metabolism*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D003600:Cytosol / Q000737:chemistry; D005234:Fatty Liver / Q000473:pathology*; D015870:Gene Expression; D055786:Gene Knockout Techniques; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D014665:Vasodilator Agents / Q000378:metabolism*
chemical_list: D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D014665:Vasodilator Agents; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7)