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FADD is a key regulator of lipid metabolism.

ABSTRACT: FADD, a classical apoptotic signaling adaptor, was recently reported to have non-apoptotic functions. Here, we report the discovery that FADD regulates lipid metabolism. PPAR-α is a dietary lipid sensor, whose activation results in hypolipidemic effects. We show that FADD interacts with RIP140, which is a corepressor for PPAR-α, and FADD phosphorylation-mimic mutation (FADD-D) or FADD deficiency abolishes RIP140-mediated transcriptional repression, leading to the activation of PPAR-α. FADD-D-mutant mice exhibit significantly decreased adipose tissue mass and triglyceride accumulation. Also, they exhibit increased energy expenditure with enhanced fatty acid oxidation in adipocytes due to the activation of PPAR-α. Similar metabolic phenotypes, such as reduced fat formation, insulin resistance, and resistance to HFD-induced obesity, are shown in adipose-specific FADD knockout mice. Additionally, FADD-D mutation can reverse the severe genetic obesity phenotype of ob/ob mice, with elevated fatty acid oxidation and oxygen consumption in adipose tissue, improved insulin resistance, and decreased triglyceride storage. We conclude that FADD is a master regulator of glucose and fat metabolism with potential applications for treatment of insulin resistance and obesity.

SUBMITTER: Zhuang H

PROVIDER: S-EPMC4967943 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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FADD is a key regulator of lipid metabolism.

Zhuang Hongqin H Wang Xueshi X Zha Daolong D Gan Ziyi Z Cai Fangfang F Du Pan P Yang Yunwen Y Yang Bingya B Zhang Xiangyu X Yao Chun C Zhou Yuqiang Y Jiang Chizhou C Guan Shengwen S Zhang Xuerui X Zhang Jing J Jiang Wenhui W Hu Qingang Q Hua Zi-Chun ZC

EMBO molecular medicine 20160801 8

FADD, a classical apoptotic signaling adaptor, was recently reported to have non-apoptotic functions. Here, we report the discovery that FADD regulates lipid metabolism. PPAR-α is a dietary lipid sensor, whose activation results in hypolipidemic effects. We show that FADD interacts with RIP140, which is a corepressor for PPAR-α, and FADD phosphorylation-mimic mutation (FADD-D) or FADD deficiency abolishes RIP140-mediated transcriptional repression, leading to the activation of PPAR-α. FADD-D-mut ...[more]

PMID: 27357657

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Project description: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 MED1 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 Med1 KD (Med1 LKD) mice under fed and fasting conditions. Together, these findings showed that Med1 played a key role in hepatic autophagy, mitochondria function, and lipid metabolism under these conditions. Additionally, we identified downregulated hepatic genes in Med1 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 Med1 LKD. Finally, Med1 expression and autophagy also were decreased in two mouse models of nonalcoholic fatty liver disease (NAFLD) suggesting that decreased Med1 may contribute to hepatosteatosis. In summary, MED1 plays an essential role in regulating hepatic autophagy and lipid oxidation during different hormonal and nutrient conditions. Thus, MED1 may serve as an integrator of multiple transcriptional pathways involved in these metabolic processes.Abbreviations: BAF: bafilomycin A1; db/db mice; Leprdb/db 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.

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FADD is a key regulator of lipid metabolism.

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FADD is a key regulator of lipid metabolism.

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