Metabolic nuclear receptors coordinate energy metabolism to regulate Sox9+ hepatocyte fate

Liu, Shenghui; Qin, Dan; Yan, Yi; Wu, Jiayan; Liu, Meng; Huang, Wendong; Wang, Liqiang; Chen, Xiangmei; Zhang, Lisheng

doi:10.1016/j.isci.2021.103003

Cited by 9 publications

(4 citation statements)

References 60 publications

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“…In recent years, the role of Sox9 + hepatocytes in chronic liver injury repair has been widely documented [ 10 , 38 ], but the role of Sox9 + hepatocytes in acute liver injury repair has rarely been reported. Hepatic IRI model was applied to investigate the function of Sox9 + hepatocytes in acute liver injury repair.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, Font-Burgada et al have found that Sox9 is also expressed in a subset of hepatocytes, and Sox9 + hepatocytes are present around the ductal plate, and they are also known as hybrid hepatocytes (HybHP), because they jointly express cholangiocyte-specific marker CK19 and key hepatocyte marker HNF4α, and they proliferate extensively in response to chronic hepatocyte-depleting injuries [ 9 ]. Our previous studies indicate that Sox9 + hepatocytes can serve as bipotent progenitors to repair the liver after chronic liver injury [ 10 , 11 ]. However, the role and mechanism underlying the Sox9 + hepatocytes in response to the acute liver injury have not been elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Hepatocyte-specific Sox9 knockout ameliorates acute liver injury by suppressing SHP signaling and improving mitochondrial function

Qin,

Wang,

et al. 2023

Cell Biosci

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Background and Aims Sex determining region Y related high-mobility group box protein 9 (Sox9) is expressed in a subset of hepatocytes, and it is important for chronic liver injury. However, the roles of Sox9+ hepatocytes in response to the acute liver injury and repair are poorly understood. Methods In this study, we developed the mature hepatocyte-specific Sox9 knockout mouse line and applied three acute liver injury models including PHx, CCl4 and hepatic ischemia reperfusion (IR). Huh-7 cells were subjected to treatment with hydrogen peroxide (H2O2) in order to induce cellular damage in an in vitro setting. Results We found the positive effect of Sox9 deletion on acute liver injury repair. Small heterodimer partner (SHP) expression was highly suppressed in hepatocyte-specific Sox9 deletion mouse liver, accompanied by less cell death and more cell proliferation. However, in mice with hepatocyte-specific Sox9 deletion and SHP overexpression, we observed an opposite phenotype. In addition, the overexpression of SOX9 in H2O2-treated Huh-7 cells resulted in an increase in cytoplasmic SHP accumulation, accompanied by a reduction of SHP in the nucleus. This led to impaired mitochondrial function and subsequent cell death. Notably, both the mitochondrial dysfunction and cell damage were reversed when SHP siRNA was employed, indicating the crucial role of SHP in mediating these effects. Furthermore, we found that Sox9, as a vital transcription factor, directly bound to SHP promoter to regulate SHP transcription. Conclusions Overall, our findings unravel the mechanism by which hepatocyte-specific Sox9 knockout ameliorates acute liver injury via suppressing SHP signaling and improving mitochondrial function. This study may provide a new treatment strategy for acute liver injury in future. Graphical Abstract

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hepatocyte-specific Sox9 knockout ameliorates acute liver injury by suppressing SHP signaling and improving mitochondrial function

Qin,

Wang,

et al. 2023

Cell Biosci

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“…Isolation of Primary Mouse Hepatocytes and Cell Sorting: Primary mouse hepatocytes were isolated by the previously reported method with minor modification. [46] Briefly, the WT and LKO mice were anesthetized with Avertin (Sigma-Aldrich, T48402, 240 mg kg −1 ) by intraperitoneal injection, and the hepatic portal vein was cannulated. The liver was perfused at 6 mL min −1 with pre-warmed perfusion medium containing EGTA for 8 min.…”

Section: Methodsmentioning

confidence: 99%

MSL1 Promotes Liver Regeneration by Driving Phase Separation of STAT3 and Histone H4 and Enhancing Their Acetylation

He,

Wang,

Liu

et al. 2023

Advanced Science

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Male‐specific lethal 1 (MSL1) is critical for the formation of MSL histone acetyltransferase complex which acetylates histone H4 Lys16 (H4K16ac) to activate gene expression. However, the role of MSL1 in liver regeneration is poorly understood. Here, this work identifies MSL1 as a key regulator of STAT3 and histone H4 (H4) in hepatocytes. MSL1 forms condensates with STAT3 or H4 through liquid–liquid phase separation to enrich acetyl‐coenzyme A (Ac‐CoA), and Ac‐CoA in turn enhances MSL1 condensate formation, synergetically promoting the acetylation of STAT3 K685 and H4K16, thus stimulating liver regeneration after partial hepatectomy (PH). Additionally, increasing Ac‐CoA level can enhance STAT3 and H4 acetylation, thus promoting liver regeneration in aged mice. The results demonstrate that MSL1 condensate‐mediated STAT3 and H4 acetylation play an important role in liver regeneration. Thus, promoting the phase separation of MSL1 and increasing Ac‐CoA level may be a novel therapeutic strategy for acute liver diseases and transplantation.

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“…Consequently, this facilitates the regeneration of Sox9+ hepatocytes that assume the role of bidirectional progenitor cells following liver injury. These cells can give rise to hepatocytes or bile duct cells, contributing to liver repair and regeneration [ 149 , 150 ]. Furthermore, specific FXR knockout in hepatocytes significantly delays the initiation signal of growth factors, hampering liver regeneration [ 151 ].…”

Section: Pharmacology Of Fxr In Liver Fibrosismentioning

confidence: 99%

Farnesoid X receptor: From Structure to Function and Its Pharmacology in Liver Fibrosis

Ding,

Wang,

Dou

et al. 2023

Aging and disease

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The farnesoid X receptor (FXR), a ligand-activated transcription factor, plays a crucial role in regulating bile acid metabolism within the enterohepatic circulation. Beyond its involvement in metabolic disorders and immune imbalances affecting various tissues, FXR is implicated in microbiota modulation, gut-to-brain communication, and liver disease. The liver, as a pivotal metabolic and detoxification organ, is susceptible to damage from factors such as alcohol, viruses, drugs, and high-fat diets. Chronic or recurrent liver injury can culminate in liver fibrosis, which, if left untreated, may progress to cirrhosis and even liver cancer, posing significant health risks. However, therapeutic options for liver fibrosis remain limited in terms of FDA-approved drugs. Recent insights into the structure of FXR, coupled with animal and clinical investigations, have shed light on its potential pharmacological role in hepatic fibrosis. Progress has been achieved in both fundamental research and clinical applications. This review critically examines recent advancements in FXR research, highlighting challenges and potential mechanisms underlying its role in liver fibrosis treatment.

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Metabolic nuclear receptors coordinate energy metabolism to regulate Sox9+ hepatocyte fate

Cited by 9 publications

References 60 publications

Hepatocyte-specific Sox9 knockout ameliorates acute liver injury by suppressing SHP signaling and improving mitochondrial function

Hepatocyte-specific Sox9 knockout ameliorates acute liver injury by suppressing SHP signaling and improving mitochondrial function

MSL1 Promotes Liver Regeneration by Driving Phase Separation of STAT3 and Histone H4 and Enhancing Their Acetylation

Farnesoid X receptor: From Structure to Function and Its Pharmacology in Liver Fibrosis

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