Program of Cardiovascular & Metabolic Disorders, Duke-NUS Medical School Singapore, Singapore.
Department of Endocrinology and Metabolism, Amsterdam UMC, Amsterdam, The Netherlands.
Autophagy. 2021 Dec;17(12):4043-4061. doi: 10.1080/15548627.2021.1899691. Epub 2021 Mar 18.
Hepatic macroautophagy/autophagy and fatty acid metabolism are transcriptionally regulated by nuclear receptors (NRs); however, it is not known whether their transcriptional co-activators are involved in autophagy. We thus examined MED1 (mediator complex subunit 1), a key component of the Mediator Complex that directly interacts with NRs, on these processes. We found that knockdown (KD) in cultured hepatic cells decreased autophagy and mitochondrial activity that was accompanied by decreased transcription of genes involved in these processes. Lipophagy and fatty acid β-oxidation also were impaired. These effects also occurred after thyroid hormone stimulation, nutrient-replete or -deplete conditions, and in liver-specific KD ( LKD) mice under fed and fasting conditions. Together, these findings showed that played a key role in hepatic autophagy, mitochondria function, and lipid metabolism under these conditions. Additionally, we identified downregulated hepatic genes in LKD mice, and subjected them to ChIP Enrichment Analysis. Our findings showed that the transcriptional activity of several NRs and transcription factors (TFs), including PPARA and FOXO1, likely were affected by LKD. Finally, expression and autophagy also were decreased in two mouse models of nonalcoholic fatty liver disease (NAFLD) suggesting that decreased may contribute to hepatosteatosis. In summary, plays an essential role in regulating hepatic autophagy and lipid oxidation during different hormonal and nutrient conditions. Thus, may serve as an integrator of multiple transcriptional pathways involved in these metabolic processes. BAF: bafilomycin A; db/db mice; mice; ECAR: extracellular acidification rate; KD: knockdown; MED1: mediator complex subunit 1; NAFLD: nonalcoholic fatty liver disease; OCR: oxygen consumption rate; PPARA/PPARα: peroxisomal proliferator activated receptor alpha; TF: transcription factor; TFEB: transcription factor EB; tf-LC3: tandem fluorescence RFP-GFP-LC3; TG: triglyceride; TH: Thyroid hormone; TR: thyroid hormone receptors; V-ATPase: vacuolar-type H-ATPase; WDF: Western diet with 15% fructose in drinking water.
肝巨自噬/自噬和脂肪酸代谢受核受体（NRs）转录调控；然而，其转录共激活因子是否参与自噬尚不清楚。因此，我们研究了 MED1（中介复合物亚基 1），一种与 NRs 直接相互作用的中介复合物的关键组成部分，以检查其在这些过程中的作用。我们发现，在培养的肝细胞中敲低（KD）会降低自噬和线粒体活性，同时伴随参与这些过程的基因转录减少。脂自噬和脂肪酸β氧化也受到损害。这些影响也发生在甲状腺激素刺激、营养丰富或缺乏以及在喂食和禁食条件下肝特异性 KD（LKD）小鼠中。总之，这些发现表明，在这些条件下， 在肝自噬、线粒体功能和脂质代谢中发挥关键作用。此外，我们鉴定了 LKD 小鼠中下调的肝基因，并对其进行了 ChIP 富集分析。我们的研究结果表明，几种 NRs 和转录因子（TFs）的转录活性，包括 PPARA 和 FOXO1，可能受到 LKD 的影响。最后，两种非酒精性脂肪性肝病（NAFLD）小鼠模型中 的表达和自噬也减少，表明 的减少可能导致肝脂肪变性。总之， 在调节不同激素和营养条件下的肝自噬和脂质氧化中发挥重要作用。因此， 可能是参与这些代谢过程的多个转录途径的整合因子。BAF：巴弗洛霉素 A；db/db 小鼠； 小鼠；ECAR：细胞外酸化率；KD：敲低；MED1：中介复合物亚基 1；NAFLD：非酒精性脂肪性肝病；OCR：耗氧量；PPARA/PPARα：过氧化物酶体增殖物激活受体α；TF：转录因子；TFEB：转录因子 EB；tf-LC3：串联荧光 RFP-GFP-LC3；TG：甘油三酯；TH：甲状腺激素；TR：甲状腺激素受体；V-ATPase：液泡型 H+-ATP 酶；WDF：含 15%果糖的西方饮食饮用水。
