TMEM135缺乏通过sirt1依赖的方式抑制CD36来改善肝脂肪变性。

IF 7 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism Pub Date : 2025-02-01 DOI:10.1016/j.molmet.2024.102080

Arun Chhetri , Channy Park , Hyunsoo Kim , Laxman Manandhar , Chagtsalmaa Chuluunbaatar , Jaetaek Hwang , Xiaofan Wei , Gyuho Jang , Batching Chinbold , Hyug Moo Kwon , Sang-wook Lee , Raekil Park

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引用次数: 0

摘要

目的：脂质稳态通路失调可引起包括肝脂肪变性在内的多种肝脏疾病。导致脂质积累的主要因素之一是肝脏对脂肪酸的摄取。跨膜蛋白135 （TMEM135）存在于线粒体和过氧化物酶体中，参与细胞内脂质代谢。本研究旨在探讨TMEM135在调节肝脏细胞脂质进口中的作用。方法：采用体内、离体和体外脂肪变性模型。TMEM135敲除小鼠（TMEM135KO）和野生型小鼠（WT）喂食高脂肪饮食（HFD）诱导肝脏脂肪变性。用游离脂肪酸（FFA）处理小鼠原代肝细胞和AML12细胞。此外，利用AML12细胞建立了tmem135缺失的稳定细胞和过表达细胞。结果：TMEM135缺乏减轻了hfd喂养的TMEM135KO小鼠肝脏中的脂质积累。与对照细胞相比，经FFA处理的tmem135缺失的原代肝细胞和AML12细胞的脂质积累较少，如脂滴所示。与此一致的是，在TMEM135过表达条件下，TMEM135缺失对脂质积累的影响完全逆转。HFD或FFA显著诱导CD36表达，TMEM135缺失后CD36表达降低。在SIRT家族蛋白中，只有SIRT1在饲喂hfd的TMEM135KO小鼠肝脏中表达明显升高，NAD+/NADH比值显著升高。然而，在tmem135缺失的细胞中，使用siSIRT1或SIRT1抑制剂Ex-527抑制SIRT1会导致CD36表达增加，从而导致TG水平升高。结论：TMEM135缺失以sirt1依赖的方式减弱CD36的表达，从而减少细胞脂质摄取和肝脏脂肪变性。

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TMEM135 deficiency improves hepatic steatosis by suppressing CD36 in a SIRT1-dependent manner

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TMEM135 deficiency improves hepatic steatosis by suppressing CD36 in a SIRT1-dependent manner

Objectives

Dysregulation of lipid homeostasis pathway causes many liver diseases, including hepatic steatosis. One of the primary factors contributing to lipid accumulation is fatty acid uptake by the liver. Transmembrane protein 135 (TMEM135), which exists in mitochondria and peroxisomes, participates in intracellular lipid metabolism. This study aims to investigate the role of TMEM135 on regulating cellular lipid import in the liver.

Methods

We used in vivo, ex vivo, and in vitro models of steatosis. TMEM135 knockout (TMEM135KO) and wild type (WT) mice were fed a high-fat diet (HFD) to induce hepatic steatosis. Primary mouse hepatocytes and AML12 cells were treated with free fatty acid (FFA). Additionally, TMEM135-deficient stable cells and overexpressed cells were established using AML12 cells.

Results

TMEM135 deficiency mitigated lipid accumulation in the liver of HFD-fed TMEM135KO mice. TMEM135-depleted primary hepatocytes and AML12 cells exhibited less lipid accumulation when treated with FFA compared to control cells, as shown as lipid droplets. Consistently, the effect of TMEM135 depletion on lipid accumulation was completely reversed under TMEM135 overexpression conditions. CD36 expression was markedly induced by HFD or FFA, which was reduced by TMEM135 depletion. Among the SIRT family proteins, only SIRT1 expression definitely increased in the liver of HFD-fed TMEM135KO mice along with a significant increase in NAD⁺/NADH ratio. However, inhibition of SIRT1 in TMEM135-depleted cells using siSIRT1 or the SIRT1 inhibitor EX-527 resulted in an increase of CD36 expression and consequent TG levels.

Conclusions

TMEM135 depletion attenuates CD36 expression in a SIRT1-dependent manner, thereby reducing cellular lipid uptake and hepatic steatosis.

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来源期刊

Molecular Metabolism ENDOCRINOLOGY & METABOLISM-

CiteScore

14.50

自引率

2.50%

发文量

219

审稿时长

43 days

期刊介绍： Molecular Metabolism is a leading journal dedicated to sharing groundbreaking discoveries in the field of energy homeostasis and the underlying factors of metabolic disorders. These disorders include obesity, diabetes, cardiovascular disease, and cancer. Our journal focuses on publishing research driven by hypotheses and conducted to the highest standards, aiming to provide a mechanistic understanding of energy homeostasis-related behavior, physiology, and dysfunction. We promote interdisciplinary science, covering a broad range of approaches from molecules to humans throughout the lifespan. Our goal is to contribute to transformative research in metabolism, which has the potential to revolutionize the field. By enabling progress in the prognosis, prevention, and ultimately the cure of metabolic disorders and their long-term complications, our journal seeks to better the future of health and well-being.