☆ 4.8 Article

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

AUTOPHAGY (2021)

Journal

AUTOPHAGY

Volume 17, Issue 12, Pages 4043-4061

Publisher

TAYLOR & FRANCIS INC

DOI: 10.1080/15548627.2021.1899691

Keywords

Autophagy; lipid oxidation; liver; med1; starvation

Funding

National Medical Research Council [NMRC/OFYIRG/0002/2016, MOH-000319, MOH-000306]
Duke-NUS Medical School
Estate of Tan Sri Khoo Teck Puat Khoo Pilot Award [Duke-NUS-KP (Coll)/2018/0007A]

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Abstract

The study demonstrated that MED1 plays a crucial role in regulating hepatic autophagy, mitochondria function, and lipid metabolism. It may affect the transcriptional activity of various NRs and transcription factors, and contribute to the development of nonalcoholic fatty liver disease.

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.

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Metabolome Characteristics of Liver Autophagy Deficiency under Starvation Conditions in Infancy

Kazuhito Sekiguchi, Hiroaki Miyahara, Masanori Inoue, Kyoko Kiyota, Kumiko Sakai, Toshikatsu Hanada, Kenji Ihara

Summary: The study found that liver autophagy is not essential for the survival of neonatal mice under starvation conditions, as they can adapt to changes in metabolic pathways, such as the malate-aspartate shuttle, aspartate metabolism, urea cycle, and glycine and serine metabolism. This adaptation may involve a change in mitochondrial function to maintain ketone production and avoid fatal starvation.

NUTRIENTS (2021)