PMID- 33734012
OWN - NLM
STAT- MEDLINE
DCOM- 20220407
LR  - 20220531
IS  - 1554-8635 (Electronic)
IS  - 1554-8627 (Print)
IS  - 1554-8627 (Linking)
VI  - 17
IP  - 12
DP  - 2021 Dec
TI  - MED1 mediator subunit is a key regulator of hepatic autophagy and lipid 
      metabolism.
PG  - 4043-4061
LID - 10.1080/15548627.2021.1899691 [doi]
AB  - 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 beta-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 A(1); db/db 
      mice; Lepr(db/db) mice; ECAR: extracellular acidification rate; KD: knockdown; 
      MED1: mediator complex subunit 1; NAFLD: nonalcoholic fatty liver disease; OCR: 
      oxygen consumption rate; PPARA/PPARalpha: 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.
FAU - Zhou, Jin
AU  - Zhou J
AD  - Program of Cardiovascular & Metabolic Disorders, Duke-NUS Medical School 
      Singapore, Singapore.
FAU - Singh, Brijesh K
AU  - Singh BK
AD  - Program of Cardiovascular & Metabolic Disorders, Duke-NUS Medical School 
      Singapore, Singapore.
FAU - Ho, Jia Pei
AU  - Ho JP
AD  - Program of Cardiovascular & Metabolic Disorders, Duke-NUS Medical School 
      Singapore, Singapore.
FAU - Lim, Andrea
AU  - Lim A
AD  - Program of Cardiovascular & Metabolic Disorders, Duke-NUS Medical School 
      Singapore, Singapore.
FAU - Bruinstroop, Eveline
AU  - Bruinstroop E
AUID- ORCID: 0000-0001-6466-8497
AD  - Department of Endocrinology and Metabolism, Amsterdam UMC, Amsterdam, The 
      Netherlands.
FAU - Ohba, Kenji
AU  - Ohba K
AUID- ORCID: 0000-0001-8538-8742
AD  - Program of Cardiovascular & Metabolic Disorders, Duke-NUS Medical School 
      Singapore, Singapore.
FAU - Sinha, Rohit A
AU  - Sinha RA
AD  - Program of Cardiovascular & Metabolic Disorders, Duke-NUS Medical School 
      Singapore, Singapore.
AD  - Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical 
      Sciences, Lucknow India.
FAU - Yen, Paul M
AU  - Yen PM
AD  - Program of Cardiovascular & Metabolic Disorders, Duke-NUS Medical School 
      Singapore, Singapore.
AD  - Duke Molecular Physiology Institute and Department of Medicine, Duke University 
      Medical Center, Durham, NC USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210318
PL  - United States
TA  - Autophagy
JT  - Autophagy
JID - 101265188
RN  - 0 (Med1 protein, mouse)
RN  - 0 (Mediator Complex Subunit 1)
RN  - 0 (PPAR alpha)
SB  - IM
MH  - Animals
MH  - Autophagy/genetics
MH  - *Lipid Metabolism/genetics
MH  - Liver/metabolism
MH  - Mediator Complex Subunit 1/genetics/metabolism
MH  - Mice
MH  - *Non-alcoholic Fatty Liver Disease/genetics
MH  - PPAR alpha/metabolism
PMC - PMC8726716
OTO - NOTNLM
OT  - Autophagy
OT  - lipid oxidation
OT  - liver
OT  - med1
OT  - starvation
COIS- The authors have no conflict of interest.
EDAT- 2021/03/19 06:00
MHDA- 2022/04/08 06:00
PMCR- 2022/03/18
CRDT- 2021/03/18 12:31
PHST- 2021/03/19 06:00 [pubmed]
PHST- 2022/04/08 06:00 [medline]
PHST- 2021/03/18 12:31 [entrez]
PHST- 2022/03/18 00:00 [pmc-release]
AID - 1899691 [pii]
AID - 10.1080/15548627.2021.1899691 [doi]
PST - ppublish
SO  - Autophagy. 2021 Dec;17(12):4043-4061. doi: 10.1080/15548627.2021.1899691. Epub 
      2021 Mar 18.