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MED1 mediator subunit is a key regulator of hepatic autophagy and lipid metabolism.

Publication ,  Journal Article
Zhou, J; Singh, BK; Ho, JP; Lim, A; Bruinstroop, E; Ohba, K; Sinha, RA; Yen, PM
Published in: Autophagy
December 2021

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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Published In

Autophagy

DOI

EISSN

1554-8635

Publication Date

December 2021

Volume

17

Issue

12

Start / End Page

4043 / 4061

Location

United States

Related Subject Headings

  • PPAR alpha
  • Non-alcoholic Fatty Liver Disease
  • Mice
  • Mediator Complex Subunit 1
  • Liver
  • Lipid Metabolism
  • Biochemistry & Molecular Biology
  • Autophagy
  • Animals
  • 3101 Biochemistry and cell biology
 

Citation

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Zhou, J., Singh, B. K., Ho, J. P., Lim, A., Bruinstroop, E., Ohba, K., … Yen, P. M. (2021). MED1 mediator subunit is a key regulator of hepatic autophagy and lipid metabolism. Autophagy, 17(12), 4043–4061. https://doi.org/10.1080/15548627.2021.1899691
Zhou, Jin, Brijesh K. Singh, Jia Pei Ho, Andrea Lim, Eveline Bruinstroop, Kenji Ohba, Rohit A. Sinha, and Paul M. Yen. “MED1 mediator subunit is a key regulator of hepatic autophagy and lipid metabolism.Autophagy 17, no. 12 (December 2021): 4043–61. https://doi.org/10.1080/15548627.2021.1899691.
Zhou J, Singh BK, Ho JP, Lim A, Bruinstroop E, Ohba K, et al. MED1 mediator subunit is a key regulator of hepatic autophagy and lipid metabolism. Autophagy. 2021 Dec;17(12):4043–61.
Zhou, Jin, et al. “MED1 mediator subunit is a key regulator of hepatic autophagy and lipid metabolism.Autophagy, vol. 17, no. 12, Dec. 2021, pp. 4043–61. Pubmed, doi:10.1080/15548627.2021.1899691.
Zhou J, Singh BK, Ho JP, Lim A, Bruinstroop E, Ohba K, Sinha RA, Yen PM. MED1 mediator subunit is a key regulator of hepatic autophagy and lipid metabolism. Autophagy. 2021 Dec;17(12):4043–4061.

Published In

Autophagy

DOI

EISSN

1554-8635

Publication Date

December 2021

Volume

17

Issue

12

Start / End Page

4043 / 4061

Location

United States

Related Subject Headings

  • PPAR alpha
  • Non-alcoholic Fatty Liver Disease
  • Mice
  • Mediator Complex Subunit 1
  • Liver
  • Lipid Metabolism
  • Biochemistry & Molecular Biology
  • Autophagy
  • Animals
  • 3101 Biochemistry and cell biology