Hepatic CREBZF couples insulin to lipogenesis by inhibiting insig activity and contributes to hepatic steatosis in diet‐induced insulin‐resistant mice

Zhang, Feifei; Hu, Zhimin; Li, Gaopeng; Huo, Shaofeng; Ma, Fengguang; Cui, Aoyuan; Xue, Yaqian; Han, Yamei; Gong, Qiyong; Gao, Jing; Bian, Hua; Meng, Zhuo-Xian; Wu, Haifu; Long, Gang; Tan, Yi; Zhang, Yan; Lin, Xu; Gao, Xin; Xu, Aimin; Yu, Lap-Fai

doi:10.1002/hep.29926

Cited by 44 publications

(56 citation statements)

References 37 publications

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“…CREBZF gain‐of‐function and loss‐of‐function approaches demonstrate an inhibitory action of CREBZF on STAT3 activity in mouse livers, primary hepatocytes, and several cell lines. These findings are consistent with the actions of CREBZF as an inhibitor for Insig‐2a to promote sustained lipogenesis in response to refeeding or during diet‐induced obesity in mice . Our results demonstrate a dimerization‐dependent but phosphorylation‐independent regulation of CREBZF on STAT3 activity.…”

Section: Discussionsupporting

confidence: 89%

“…These findings are consistent with the actions of CREBZF as an inhibitor for Insig2a to pro mote sustained lipogenesis in response to refeed ing or during dietinduced obesity in mice. (15) Our results demonstrate a dimerizationdependent but phosphorylationindependent regulation of CREBZF on STAT3 activity. Mechanistically, CREBZF inhib its dimerization and activation of STAT3, resulting in a reduction of cell cycle gene expression.…”

Section: Crebzf Acts As a Negative Regulator Of The Stat3 Pathwaymentioning

confidence: 49%

“…Recently, we reported that CREBZF enhances sustained lipogenesis in the liver in response to refeeding or under selective insulin resistance con ditions. (15) Interestingly, another bZIP transcription factor CCAAT enhancerbinding protein β has been shown to increase hepatocyte proliferation in mice after partial hepatectomy, which was correlated with an alteration of hepatic gluconeogenesis and glucose homeostasis. (44) These data indicate that bZIP tran scription factors play an important role in the reg ulation of liver regeneration.…”

Section: Crebzf Regulates Liver Regenerationmentioning

confidence: 99%

“…These data suggest that CREBZF plays an important role in regulating lipid metabolism, and that hyperactivation of CREBZF may be linked to the pathogenesis of NAFLD and dyslipidemia in humans. CREBZF functions as a transcriptional coregulator of other transcriptional factors or nuclear receptors, including ATF4, CREB3/Luman, and glucocorticoid receptor . Given the increased number of liver transplant candidates and severe shortage of available organs, it is urgently needed to develop therapeutic approaches to prevent steatosis‐related complications and improve the clinical outcome of liver transplantation .…”

mentioning

confidence: 99%

“…In response to acute injury or resection, the quiescent hepatocytes can be triggered to regenerate and restore tissue homeostasis. (15) The understanding of the mechanisms that regulate the process of liver regeneration is important to promote regeneration and prevent clinical complications during liver transplantation. Recent studies have shown that liver regeneration is exquisitely controlled by well orchestrated signaling pathways involving cytokines, growth factors, and metabolic networks.…”

mentioning

confidence: 99%

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CREBZF as a Key Regulator of STAT3 Pathway in the Control of Liver Regeneration in Mice

Han

Liu

et al. 2020

Hepatology

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Background and Aims STAT3, a member of the signal transducer and activator of transcription (STAT) family, is strongly associated with liver injury, inflammation, regeneration, and hepatocellular carcinoma development. However, the signals that regulate STAT3 activity are not completely understood. Approach and Results Here we characterize CREB/ATF bZIP transcription factor CREBZF as a critical regulator of STAT3 in the hepatocyte to repress liver regeneration. We show that CREBZF deficiency stimulates the expression of the cyclin gene family and enhances liver regeneration after partial hepatectomy. Flow cytometry analysis reveals that CREBZF regulates cell cycle progression during liver regeneration in a hepatocyte‐autonomous manner. Similar results were observed in another model of liver regeneration induced by intraperitoneal injection of carbon tetrachloride (CCl4). Mechanistically, CREBZF potently associates with the linker domain of STAT3 and represses its dimerization and transcriptional activity in vivo and in vitro. Importantly, hepatectomy‐induced hyperactivation of cyclin D1 and liver regeneration in CREBZF liver‐specific knockout mice was reversed by selective STAT3 inhibitor cucurbitacin I. In contrast, adeno‐associated virus–mediated overexpression of CREBZF in the liver inhibits the expression of the cyclin gene family and attenuates liver regeneration in CCl4‐treated mice. Conclusions These results characterize CREBZF as a coregulator of STAT3 to inhibit regenerative capacity, which may represent an essential cellular signal to maintain liver mass homeostasis. Therapeutic approaches to inhibit CREBZF may benefit the compromised liver during liver transplantation.

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Section: Discussionsupporting

confidence: 89%

Section: Crebzf Acts As a Negative Regulator Of The Stat3 Pathwaymentioning

confidence: 49%

Section: Crebzf Regulates Liver Regenerationmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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CREBZF as a Key Regulator of STAT3 Pathway in the Control of Liver Regeneration in Mice

Han

Liu

et al. 2020

Hepatology

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Macrophage CREBZF Orchestrates Inflammatory Response to Potentiate Insulin Resistance and Type 2 Diabetes

Liu,

Su,

Liu

et al. 2024

Advanced Science

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Chronic adipose tissue inflammation accompanied by macrophage accumulation and activation is implicated in the pathogenesis of insulin resistance and type 2 diabetes in humans. The transcriptional coregulator CREBZF is a key factor in hepatic metabolism, yet its role in modulating adipose tissue inflammation and type 2 diabetes remains elusive. The present study demonstrates that overnutrition‐induced CREBZF links adipose tissue macrophage (ATM) proinflammatory activation to insulin resistance. CREBZF deficiency in macrophages, not in neutrophils, attenuates macrophage infiltration in adipose, proinflammatory activation, and hyperglycemia in diet‐induced insulin‐resistant mice. The coculture assays show that macrophage CREBZF deficiency improves insulin sensitivity in primary adipocytes and adipose tissue. Mechanistically, CREBZF competitively inhibits the binding of IκBα to p65, resulting in enhanced NF‐κB activity. In addition, bromocriptine is identified as a small molecule inhibitor of CREBZF in macrophages, which suppresses the proinflammatory phenotype and improves metabolic dysfunction. Furthermore, CREBZF is highly expressed in ATM of obese humans and mice, which is positively correlated with proinflammatory genes and insulin resistance in humans. This study identifies a previously unknown role of CREBZF coupling ATM activation to systemic insulin resistance and type 2 diabetes.

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Improvement of Non‐Alcoholic Fatty Liver Disease in Mice by Intermittent Use of a Fasting‐Mimicking Diet

Zhao

Bai

Wei

et al. 2021

Molecular Nutrition Food Res

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Scope: Liver plays a central role in maintaining lipid homeostasis which is dysregulated in non-alcoholic fatty liver disease (NAFLD) caused by overload of dietary fat, increase in lipid synthesis, and alteration of fatty acid oxidation in the liver. In this study, we aimed to investigate whether intermittent calorie restriction using a fasting-mimicking diet (FMD) is able to slow down the progression of NAFLD in mice. Methods and Results: This study analyzed the intervention activity of a FMD low in carbohydrate/protein but high in dietary fibers with a NAFLD mouse model induced by high-fat high-sucrose diet (HFHSD). Intermittent application of the FMD reduces HFHSD-induced obesity and glucose intolerance. The FMD decreases the size of adipocytes and elevates expression of lipolysis genes and HSL protein in white adipose tissue. HFHSD-induced lipid accumulation in the liver is reduced by the FMD, accompanied by a reduction of macrophage marker in the liver. RNA sequencing reveals that the expression of a number of genes involved in fatty acid oxidation is elevated by the FMD. Conclusion: The findings indicate that intermittent application of the FMD can improve NAFLD, at least in part, through increased lipolysis in white adipose tissue and elevated fatty acid oxidation in the liver.

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Hepatic CREBZF couples insulin to lipogenesis by inhibiting insig activity and contributes to hepatic steatosis in diet‐induced insulin‐resistant mice

Abstract: These findings uncover an unexpected mechanism that couples changes in extracellular hormonal signals to hepatic lipid homeostasis; disrupting CREBZF function may have the therapeutic potential for treating fatty liver disease and insulin resistance. (Hepatology 2018).

Cited by 44 publications

References 37 publications

CREBZF as a Key Regulator of STAT3 Pathway in the Control of Liver Regeneration in Mice

CREBZF as a Key Regulator of STAT3 Pathway in the Control of Liver Regeneration in Mice

Macrophage CREBZF Orchestrates Inflammatory Response to Potentiate Insulin Resistance and Type 2 Diabetes

Improvement of Non‐Alcoholic Fatty Liver Disease in Mice by Intermittent Use of a Fasting‐Mimicking Diet

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