<i>MED1</i> mediator subunit is a key regulator of hepatic autophagy and lipid metabolism

Zhou, Jin; Singh, Brijesh Kumar; Ho, Jia Pei; Lim, Andrea; Bruinstroop, Eveline; Ohba, Kenji; Sinha, Rohit Anthony; Yen, Paul M.

doi:10.1080/15548627.2021.1899691

Cited by 22 publications

(19 citation statements)

References 50 publications

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“…This also indicated that the later increase in the Rplp1, Lamp2, and Ctsd might be required to sustain autophagy. The data is consistent with other protein Med1 (a co-activator protein) during 48 and 72 h serum starvation, that has recently been shown to be an important autophagy coactivator 31 . Previously, Esrra has been shown to positively regulate autophagy various cells 28,33,46 , while Esrra-dependent inhibition was also shown during cancers and neuroprotection 47,48,49 .…”

Section: Discussionsupporting

confidence: 89%

“…We next examined the translation rates of autophagy proteins during serum starvation by analyzing puromycin-incorporated proteins (Figure 2D). We observed a slight increase in puromycin-incorporated Map1lc3b-ii at 48 h serum starvation that was markedly increased at 72 h. Several other autophagy-related proteins, Sqstm1 and Atg5 as well as Med1 (a co-activator protein involved in stimulating autophagy) 31 had a similar temporal puromycin incorporation patterns; however, Atg7 puromycin incorporation increased at 48h and did not change between 48 and 72 h serum starvation. Significantly, proteomic analysis also revealed that Map1lc3b, Sqstm1, Atg5, and Med1 increased at 72 h of serum starvation compared to 48 h whereas Atg7 remained the same at 72 h (Supplementary Figure 2A).…”

Section: Expression Of Autophagy Proteins Were Temporally Regulated During Chronic Serum Starvation and Associated With Esrra-rplp1 Axismentioning

confidence: 69%

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Esrra regulates Rplp1-mediated translation of lysosome proteins suppressed in non-alcoholic steatohepatitis and reversed by alternate day fasting

Tripathi

Gauthier

Sandireddy

et al. 2021

Preprint

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Although general translation declines during fasting, maintaining the translation of a subset or proteins is necessary for metabolic homeostasis and cell viability. Using unbiased proteome analysis of hepatic cells during starvation, we identified a novel pathway in which Esrra-mediated transcription of Rplp1-dependent translation of lysosomal proteins declined during early starvation and recovered after prolonged starvation to restore autophagy-lysosome function. Interestingly, hepatic Esrra-Rplp1-dependent translation rate of lysosomal proteins also was impaired in patients and mice with non-alcoholic steatohepatitis (NASH), and translational response to starvation was dysregulated in mice with NASH. Remarkably, activation of Esrra pharmacologically, genetically, or by alternate day fasting restored protein translation, increased expression of lysosomal proteins, induced autophagy, and reduced lipotoxicity, inflammation, and fibrosis in cell culture and in vivo models of NASH. Thus, hepatic Esrra is essential for ribosome-dependent translation of lysosomal proteins during starvation, and prevention of lipotoxicity and progression in NASH.Lay summaryFasting for weight loss improves non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH); however, the mechanism is not well understood. Our study shows that a nuclear protein, estrogen related receptor alpha (Esrra), increases ribosome-mediated translation of autophagy and lysosome proteins during chronic starvation to maintain essential metabolic pathways for cell survival. Surprisingly, this translational pathway is impaired during NASH with reduced lysosome-autophagy activity accompanied by increased inflammation and fibrosis gene expression in the liver. Pharmacologic, genetic and dietary activation of Esrra decreases lipid-mediated toxicity in liver cells as well as inflammation and fibrosis in livers from mice with NASH. These findings suggest that the Esrra-ribosome-lysosome pathway is important for liver response to fasting and NASH and thus may be a good therapeutic target for the treatment of NASH.

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Section: Discussionsupporting

confidence: 89%

Section: Expression Of Autophagy Proteins Were Temporally Regulated During Chronic Serum Starvation and Associated With Esrra-rplp1 Axismentioning

confidence: 69%

Esrra regulates Rplp1-mediated translation of lysosome proteins suppressed in non-alcoholic steatohepatitis and reversed by alternate day fasting

Tripathi

Gauthier

Sandireddy

et al. 2021

Preprint

Self Cite

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“…We further infected the neonatal cardiomyocytes with adenovirus encoding monomeric red fluorescent protein (mRFP)-green fluorescent protein (GFP)-LC3B, an autophagy tandem sensor that can detect autophagy flux in real-time [28]. RFP and GFP were both expressed in autophagosomes, yielding yellow signals.…”

Section: Hgs-cko Hearts Resemble Lsd With Cholesterol Accumulation An...mentioning

confidence: 99%

Hgs Deficiency Caused Restrictive Cardiomyopathy via Disrupting Proteostasis

Li¹,

Wang²,

Xin³

et al. 2022

Int. J. Biol. Sci.

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The molecular mechanisms underlying restrictive cardiomyopathy (RCM) are not fully understood. Hepatocyte growth factor-regulated tyrosine kinase substrate (HGS) is a vital element of Endosomal sorting required for transport (ESCRT), which mediates protein sorting for degradation and is crucial for protein homeostasis (proteostasis) maintenance. However, the physiological function and underlying mechanisms of HGS in RCM are unexplored. We hypothesized that HGS may play vital roles in cardiac homeostasis. Cardiomyocyte-specific Hgs gene knockout mice were generated and developed a phenotype similar to human RCM. Proteomic analysis revealed that Hgs deficiency impaired lysosomal homeostasis in cardiomyocytes. Loss of Hgs disrupted cholesterol transport and lysosomal integrity, resulting in lysosomal storage disorder (LSD) with aberrant autophagosome accumulation and protein aggregation. Suppression of protein aggregation by doxycycline treatment attenuated cardiac fibrosis, and diastolic dysfunction in Hgs-knockout mice. These findings uncovered a novel physiological role of HGS in regulating cardiac lysosomal homeostasis and proteostasis, suggesting that the deficient HGS contributes to LSD-associated RCM-like cardiomyopathy.

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“…Mediator complex subunit 1 (MED1) is a major component of the multi-subunit mediator complex that bridges nuclear receptor bound to promoter with RNA polymerase II and serves as a co-activator to increase transcription of target genes regulated by nuclear receptors [ 80 ] . MED1 regulates transcription of autophagic and mitochondrial genes to increase autophagy/lipophagy, mitochondrial OXPHOS, and β-oxidation of fatty acids [ 81 ] . Since MED1 directly interacts with THR bound to the promoter region [ 82 ] , it is necessary for transcriptional regulation of T 3 -induced genes involved in autophagy/lipophagy and mitochondrial OXPHOS [ 81 ] .…”

Section: Th Effects On Impaired Autophagy In Nafldmentioning

confidence: 99%

“…MED1 regulates transcription of autophagic and mitochondrial genes to increase autophagy/lipophagy, mitochondrial OXPHOS, and β-oxidation of fatty acids [ 81 ] . Since MED1 directly interacts with THR bound to the promoter region [ 82 ] , it is necessary for transcriptional regulation of T 3 -induced genes involved in autophagy/lipophagy and mitochondrial OXPHOS [ 81 ] . T 3 also increased the expression of β-trophin (C19orf80; also known as ANGPTL8), a protein that is critical for TH-mediated induction of hepatic lipophagy and TAG hydrolysis [ 83 ] .…”

Section: Th Effects On Impaired Autophagy In Nafldmentioning

confidence: 99%

The roles of autophagy and thyroid hormone in the pathogenesis and treatment of NAFLD

Zhou¹,

Sinha²,

Yen³

2021

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

Cited by 22 publications

References 50 publications

Esrra regulates Rplp1-mediated translation of lysosome proteins suppressed in non-alcoholic steatohepatitis and reversed by alternate day fasting

Esrra regulates Rplp1-mediated translation of lysosome proteins suppressed in non-alcoholic steatohepatitis and reversed by alternate day fasting

Hgs Deficiency Caused Restrictive Cardiomyopathy via Disrupting Proteostasis

The roles of autophagy and thyroid hormone in the pathogenesis and treatment of NAFLD

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