Restoration of lipid homeostasis between TG and PE by the LXRα-ATGL/EPT1 axis ameliorates hepatosteatosis.
Restoration of lipid homeostasis between TG and PE by the LXRα-ATGL/EPT1 axis ameliorates hepatosteatosis.
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通过LXRα-ATGL/EPT 1轴恢复TG和PE之间的脂质稳态可改善脂肪肝。
DOI：
10.1038/s41419-023-05613-6
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发表时间：
2023-02-06
影响因子：
9
通讯作者：
Tang, Lan
中科院分区：
文献类型：
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作者：
Chen, Yulian;Jiang, Huanguo;Zhan, Zhikun;Lu, Jindi;Gu, Tanwei;Yu, Ping;Liang, Weimin;Zhang, Xi;Liu, Shuwen;Bi, Huichang;Zhong, Shilong;Tang, Lan
将能量过剩引起的脂质紊乱转化为健康的脂质稳态是缓解脂肪肝的一种有前途的治疗方法。我们的临床研究发现，肥胖患者的体重指数（BMI）大于28，甘油三酯（TG）进一步升高，伴随着磷脂酰乙醇胺（PE）的进一步减少。高TG、低PE患者生存期短，预后差。肝脏X受体α（LXRα）基因敲除小鼠加重了高脂饮食（HFD）诱导的肥胖和脂质紊乱，根据肝脏脂质组学分析，使TG富集和PE降低更加明显。来自小鼠肝脏的RNA-seq显示，这些代谢障碍归因于Atgl（编码TG代谢酶ATGL）和Ept 1（编码PE合成酶EPT 1）表达的下降。机制研究发现，LXRα通过与启动子中的LXR反应元件（LXRE）直接结合来激活ATGL和EPT 1基因。此外，在他汀类药物或贝特类药物治疗中补充PE以及LXRα诱导剂（冬凌草甲素）均能改善细胞脂质沉积和脂毒性。总之，通过LXRα-ATGL/EPT 1轴恢复TG和PE的脂质稳态可能是治疗脂肪肝和代谢综合征的潜在方法。
Converting lipid disturbances in response to energy oversupply into healthy lipid homeostasis is a promising therapy to alleviate hepatosteatosis. Our clinical studies found that a further elevation of triglyceride (TG) in obese patients with the body mass index (BMI) greater than 28 was accompanied by a further reduction of phosphatidylethanolamine (PE). Shorter survival and poor prognosis were shown for the patients with high TG and low PE levels. Liver X receptor alpha (LXRα) knockout mice aggravated high-fat diet (HFD)-induced obesity and lipid disorders, making the TG enrichment and the PE decrease more pronounced according to the liver lipidomics analysis. The RNA-seq from mice liver exhibited that these metabolism disorders were attributed to the decline of Atgl (encoding the TG metabolism enzyme ATGL) and Ept1 (encoding the PE synthesis enzyme EPT1) expression. Mechanistic studies uncovered that LXRα activated the ATGL and EPT1 gene via direct binding to a LXR response element (LXRE) in the promoter. Moreover, both the supplement of PE in statin or fibrate therapy, and the LXRα inducer (oridonin) ameliorated cellular lipid deposition and lipotoxicity. Altogether, restoration of lipid homeostasis of TG and PE via the LXRα-ATGL/EPT1 axis may be a potential approach for the management of hepatosteatosis and metabolic syndrome.
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影响因子：
9
作者：
Gianni' M;Goracci L;Schlaefli A;Di Veroli A;Kurosaki M;Guarrera L;Bolis M;Foglia M;Lupi M;Tschan MP;Cruciani G;Terao M;Garattini E
通讯作者：
Garattini E
影响因子：
4.8
作者：
Gubern, Albert;Barcelo-Torns, Miquel;Claro, Enrique
通讯作者：
Claro, Enrique
影响因子：
4.8
作者：
Leonardi, Roberta;Frank, Matthew W.;Jackowski, Suzanne
通讯作者：
Jackowski, Suzanne
DOI：
10.1038/nrgastro.2017.32
发表时间：
2017-06
期刊：
Nature reviews. Gastroenterology & hepatology
影响因子：
--
作者：
Gluchowski NL;Becuwe M;Walther TC;Farese RV Jr
通讯作者：
Farese RV Jr
DOI：
10.1002/hep.32105
发表时间：
2022-01
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
通讯作者：
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