Inhibition of phospholipase D1 ameliorates hepatocyte steatosis and non-alcoholic fatty liver disease
Huan Wang,
Yushang Zhao,
Yuhualei Pan,
Aiting Yang,
Changying Li,
Song Wang,
Zhao Dong,
Mengyi Li,
Songlin Wang,
Zhongtao Zhang,
Yanbing Zhu,
Dong Zhang,
Guangyong Sun
Affiliations
Huan Wang
Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, China; Beijing Clinical Research Institute, Beijing, China
Yushang Zhao
Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, China; Beijing Clinical Research Institute, Beijing, China; National Clinical Research Center for Digestive Diseases, Beijing, China; Beijing Laboratory of Oral Health, Capital Medical University School of Basic Medicine, Beijing, China
Yuhualei Pan
Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, China; Beijing Clinical Research Institute, Beijing, China; National Clinical Research Center for Digestive Diseases, Beijing, China; Beijing Laboratory of Oral Health, Capital Medical University School of Basic Medicine, Beijing, China
Aiting Yang
Beijing Clinical Research Institute, Beijing, China; National Clinical Research Center for Digestive Diseases, Beijing, China
Changying Li
Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, China; Beijing Clinical Research Institute, Beijing, China; National Clinical Research Center for Digestive Diseases, Beijing, China; Beijing Laboratory of Oral Health, Capital Medical University School of Basic Medicine, Beijing, China
Song Wang
Beijing Clinical Research Institute, Beijing, China
Zhao Dong
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
Mengyi Li
General Surgery Department, Beijing Friendship Hospital, Capital Medical University, Beijing, China
Songlin Wang
Beijing Laboratory of Oral Health, Capital Medical University School of Basic Medicine, Beijing, China
Zhongtao Zhang
General Surgery Department, Beijing Friendship Hospital, Capital Medical University, Beijing, China
Yanbing Zhu
Beijing Clinical Research Institute, Beijing, China; Corresponding author. Address: Capital Medical University Affiliated Beijing Friendship Hospital, 95 Yongan Road, Xicheng District, Beijing 100050, China. Tel.: (8610)63139309, fax: (8610)63139421.
Dong Zhang
Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, China; Beijing Clinical Research Institute, Beijing, China; National Clinical Research Center for Digestive Diseases, Beijing, China; Beijing Laboratory of Oral Health, Capital Medical University School of Basic Medicine, Beijing, China; General Surgery Department, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Corresponding author. Address: Capital Medical University Affiliated Beijing Friendship Hospital, 95 Yongan Road, Xicheng District, Beijing 100050, China. Tel.: (8610)63139309, fax: (8610)63139421.
Guangyong Sun
Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, China; Beijing Clinical Research Institute, Beijing, China; National Clinical Research Center for Digestive Diseases, Beijing, China; Beijing Laboratory of Oral Health, Capital Medical University School of Basic Medicine, Beijing, China; Corresponding author. Address: Capital Medical University Affiliated Beijing Friendship Hospital, 95 Yongan Road, Xicheng District, Beijing 100050, China. Tel.: (8610)63139309, fax: (8610)63139421.
Background & Aims: Phospholipase D1 (PLD1), a phosphatidylcholine-hydrolysing enzyme, is involved in cellular lipid metabolism. However, its involvement in hepatocyte lipid metabolism and consequently non-alcoholic fatty liver disease (NAFLD) has not been explicitly explored. Methods: NAFLD was induced in hepatocyte-specific Pld1 knockout (Pld1(H)-KO) and littermate Pld1flox/flox (Pld1-Flox) control mice feeding a high-fat diet (HFD) for 20 wk. Changes of the lipid composition in the liver were compared. Alpha mouse liver 12 (AML12) cells and mouse primary hepatocytes were incubated with oleic acid or sodium palmitate in vitro to explore the role of PLD1 in the development of hepatic steatosis. Hepatic PLD1 expression was evaluated in liver biopsy samples in patients with NAFLD. Results: PLD1 expression levels were increased in the hepatocytes of patients with NAFLD and HFD-fed mice. Compared with Pld1-Flox mice, Pld1(H)-KO mice exhibited decreased plasma glucose and lipid levels as well as lipid accumulation in liver tissues after HFD feeding. Transcriptomic analysis showed that hepatocyte-specific deficiency of PLD1 decreased Cd36 expression in steatosis liver tissues, which was confirmed at the protein and gene levels. In vitro, specific inhibition of PLD1 with VU0155069 or VU0359595 decreased CD36 expression and lipid accumulation in oleic acid- or sodium palmitate-treated AML12 cells or primary hepatocytes. Inhibition of hepatocyte PLD1 significantly altered lipid composition, especially phosphatidic acid and lysophosphatidic acid levels in liver tissues with hepatic steatosis. Furthermore, phosphatidic acid, the downstream product of PLD1, increased the expression levels of CD36 in AML12 cells, which was reversed by a PPARγ antagonist. Conclusions: Hepatocyte-specific Pld1 deficiency ameliorates lipid accumulation and NAFLD development by inhibiting the PPARγ/CD36 pathway. PLD1 may be a new target for the treatment of NAFLD. Impact and implications: The involvement of PLD1 in hepatocyte lipid metabolism and NAFLD has not been explicitly explored. In this study, we found that the inhibition of hepatocyte PLD1 exerted potent protective effects against HFD-induced NAFLD, which were attributable to a reduction in PPARγ/CD36 pathway-mediated lipid accumulation in hepatocytes. Targeting hepatocyte PLD1 may be a new target for the treatment of NAFLD.
