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J Hepatol. 2018 Sep;69(3):705-717. doi: 10.1016/j.jhep.2018.04.006. Epub 2018 Apr 27.

CD36 palmitoylation disrupts free fatty acid metabolism and promotes tissue inflammation in non-alcoholic steatohepatitis.

Author information

1
Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, 400016 Chongqing, China.
2
Astra Zeneca-Shenzhen University Joint Institute of Nephrology, Centre for Nephrology, Shenzhen University Medical School, Shenzhen University, Shenzhen, China.
3
Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 200092 Shanghai, China.
4
Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust and UCL Institute for Liver and Digestive Health, University College London Medical School, Royal Free Campus, University College London, London NW3 2PF, United Kingdom.
5
Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London, UK.
6
John Moorhead Research Laboratory, Centre for Nephrology, University College London Medical School, Royal Free Campus, University College London, London NW3 2PF, United Kingdom.
7
Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, 400016 Chongqing, China. Electronic address: chenyaxi@cqmu.edu.cn.
8
Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, 400016 Chongqing, China; The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (CCID), Zhejiang University, 310058 Hangzhou, China; John Moorhead Research Laboratory, Centre for Nephrology, University College London Medical School, Royal Free Campus, University College London, London NW3 2PF, United Kingdom. Electronic address: x.ruan@ucl.ac.uk.

Abstract

BACKGROUND AND AIMS:

Fatty acid translocase CD36 (CD36) is a membrane protein with multiple immuno-metabolic functions. Palmitoylation has been suggested to regulate the distribution and functions of CD36, but little is known about its significance in non-alcoholic steatohepatitis (NASH).

METHODS:

Human liver tissue samples were obtained from patients undergoing liver biopsy for diagnostic purposes. CD36 knockout mice were injected with lentiviral vectors expressing wild-type CD36 or CD36 with mutated palmitoylation sites. Liver histology, immunofluorescence, mRNA expression profile, subcellular distributions and functions of CD36 protein were assessed.

RESULTS:

The localization of CD36 on the plasma membrane of hepatocytes was markedly increased in patients with NASH compared to patients with normal liver and those with simple steatosis. Increased CD36 palmitoylation and increased localization of CD36 on the plasma membrane of hepatocytes were also observed in livers of mice with NASH. Furthermore, inhibition of CD36 palmitoylation protected mice from developing NASH. The absence of palmitoylation decreased CD36 protein hydrophobicity reducing its localization on the plasma membrane as well as in lipid raft of hepatocytes. Consequently, a lack of palmitoylation decreased fatty acid uptake and CD36/Fyn/Lyn complex in HepG2 cells. Inhibition of CD36 palmitoylation not only ameliorated intracellular lipid accumulation via activation of the AMPK pathway, but also inhibited the inflammatory response through the inhibition of the JNK signaling pathway.

CONCLUSIONS:

Our findings demonstrate the key role of palmitoylation in regulating CD36 distributions and its functions in NASH. Inhibition of CD36 palmitoylation may represent an effective therapeutic strategy in patients with NASH.

LAY SUMMARY:

Fatty acid translocase CD36 (CD36) is a multifunctional membrane protein which contributes to the development of liver steatosis. In the present study, we demonstrated that the localization of CD36 on the plasma membrane of hepatocytes is increased in patients with non-alcoholic steatohepatitis. Blocking the palmitoylation of CD36 reduces CD36 distribution in hepatocyte plasma membranes and protects mice from non-alcoholic steatohepatitis. The inhibition of CD36 palmitoylation not only improved fatty acid metabolic disorders but also reduced the inflammatory response in vitro and in vivo. The present study suggests that CD36 palmitoylation is important for non-alcoholic steatohepatitis development and inhibition of CD36 palmitoylation could be used to cure non-alcoholic steatohepatitis.

KEYWORDS:

Fatty acid metabolism; Fatty acid translocase CD36; Non-alcoholic steatohepatitis; Palmitoylation

PMID:
29705240
DOI:
10.1016/j.jhep.2018.04.006
[Indexed for MEDLINE]

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