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.
Astra Zeneca-Shenzhen University Joint Institute of Nephrology, Centre for Nephrology, Shenzhen University Medical School, Shenzhen University, Shenzhen, China.
J Hepatol. 2018 Sep;69(3):705-717. doi: 10.1016/j.jhep.2018.04.006. Epub 2018 Apr 27.
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).
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.
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.
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.
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.
脂肪酸转运蛋白 CD36（CD36）是一种具有多种免疫代谢功能的膜蛋白。棕榈酰化被认为可以调节 CD36 的分布和功能，但关于其在非酒精性脂肪性肝炎（NASH）中的意义知之甚少。
从接受肝活检以进行诊断的患者中获得人肝组织样本。用表达野生型 CD36 或具有突变棕榈酰化位点的 CD36 的慢病毒载体注射 CD36 敲除小鼠。评估 CD36 蛋白的肝组织学、免疫荧光、mRNA 表达谱、亚细胞分布和功能。
与正常肝脏和单纯脂肪变性患者相比，NASH 患者肝细胞质膜上的 CD36 定位明显增加。NASH 小鼠的肝脏也观察到 CD36 棕榈酰化增加和肝细胞质膜上 CD36 定位增加。此外，抑制 CD36 棕榈酰化可防止小鼠发生 NASH。缺乏棕榈酰化会降低 CD36 蛋白疏水性，从而减少其在质膜和肝细胞质膜上的脂筏中的定位。因此，缺乏棕榈酰化会减少脂肪酸摄取和 HepG2 细胞中的 CD36/Fyn/Lyn 复合物。抑制 CD36 棕榈酰化不仅通过激活 AMPK 通路改善细胞内脂质积累，还通过抑制 JNK 信号通路抑制炎症反应。
我们的研究结果表明棕榈酰化在调节 CD36 分布及其在 NASH 中的功能方面起着关键作用。抑制 CD36 棕榈酰化可能是 NASH 患者的一种有效治疗策略。
脂肪酸转运蛋白 CD36（CD36）是一种多功能膜蛋白，可促进肝脂肪变性的发展。在本研究中，我们证明了质膜上 CD36 在肝细胞中的定位在非酒精性脂肪性肝炎患者中增加。阻断 CD36 的棕榈酰化可减少 CD36 在肝细胞质膜中的分布，并可防止小鼠发生非酒精性脂肪性肝炎。CD36 棕榈酰化的抑制不仅改善了脂肪酸代谢紊乱，而且减少了体外和体内的炎症反应。本研究表明 CD36 棕榈酰化对非酒精性脂肪性肝炎的发展很重要，抑制 CD36 棕榈酰化可用于治疗非酒精性脂肪性肝炎。
