Activating transcription factor 3 is a target molecule linking hepatic steatosis to impaired glucose homeostasis

Kim, Ji Yeon; Park, Keon Jae; Hwang, Joo Yeon; Kim, Gyu Hee; Lee, Dae Yeon; Lee, Yoo Jeong; Song, E; Yoo, Min-Gyu; Kim, Bong-Jo; Suh, Young Ho; Roh, Gu Seob; Gao, Bin; Kim, Won; Kim, Won Ho

doi:10.1016/j.jhep.2017.03.023

Cited by 59 publications

(48 citation statements)

References 23 publications

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“…ORO staining demonstrated that ATF3 knockdown substantially attenuated PA‐induced lipid deposition in KO‐CON cells (Fig. A), which lent further support to previous in vivo conclusions . Furthermore, ATF3 knockdown partially relieved the exaggerated hepatosteatosis in IRF2BP2 ‐KO cells (Fig.…”

Section: Resultssupporting

confidence: 86%

“…Recently, a study published by Kim et al corroborated the fact that ATF3 is the key molecule linking hepatic steatosis and impaired glucose homeostasis . They demonstrated that hepatic ATF3 knockdown ameliorates metabolic dysfunction and inflammatory response in the Zucker diabetic fatty rat model . Moreover, a superinduction of ATF3 expression in liver is strongly correlated with type 2 diabetes and the grade of hepatic steatosis .…”

Section: Discussionmentioning

confidence: 81%

“…C). Among them, four considerations prompted us to target ATF3 as the downstream candidate of IRF2BP2: (1) The binding of IRF2BP2 on the ATF3 gene has the highest binding peak score and is in close proximity to the transcription start site (−140 bp); (2) multiple lines of evidences have suggested a pathogenic role of ATF3 in NAFLD and insulin resistance; (3) current understanding indicates a strong preference for IRF2BP2 as a transcription repressor; and (4) ATF3 expression was increased in IRF2BP2 ‐KO cells. Indeed, the up‐regulation of ATF3 mRNA levels in hepatosteatosis models, both in vitro and in vivo , were profoundly reinforced by Irf2bp2 depletion but were conversely suppressed by Irf2bp2 overexpression, as verified by real‐time PCR examinations (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies focusing on the role of ATF3 in hepatic steatosis, glucose, and insulin homeostasis came out with contradictory conclusions . Recently, a study published by Kim et al corroborated the fact that ATF3 is the key molecule linking hepatic steatosis and impaired glucose homeostasis . They demonstrated that hepatic ATF3 knockdown ameliorates metabolic dysfunction and inflammatory response in the Zucker diabetic fatty rat model .…”

Section: Discussionmentioning

confidence: 98%

“…They demonstrated that hepatic ATF3 knockdown ameliorates metabolic dysfunction and inflammatory response in the Zucker diabetic fatty rat model . Moreover, a superinduction of ATF3 expression in liver is strongly correlated with type 2 diabetes and the grade of hepatic steatosis . Nevertheless, the precise mechanisms by which hepatic ATF3 modulates metabolic dysfunctions remain to be answered.…”

Section: Discussionmentioning

confidence: 99%

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Hepatic IRF2BP2 Mitigates Nonalcoholic Fatty Liver Disease by Directly Repressing the Transcription of ATF3

Fang

Zhang

et al. 2020

Hepatology

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Background and Aims Although knowledge regarding the pathogenesis of nonalcoholic fatty liver disease (NAFLD) has profoundly grown in recent decades, the internal restrictive mechanisms remain largely unknown. We have recently reported that the transcription repressor interferon regulatory factor‐2 binding protein 2 (IRF2BP2) is enriched in cardiomyocytes and inhibits pathological cardiac hypertrophy in mice. Notably, IRF2BP2 is abundantly expressed in hepatocytes and dramatically down‐regulated in steatotic livers, whereas the role of IRF2BP2 in NAFLD is unknown. Approach and Results Herein, using gain‐of‐function and loss‐of‐function approaches in mice, we demonstrated that while hepatocyte‐specific Irf2bp2 knockout exacerbated high‐fat diet–induced hepatic steatosis, insulin resistance and inflammation, hepatic Irf2bp2 overexpression protected mice from these metabolic disorders. Moreover, the inhibitory role of IRF2BP2 on hepatosteatosis is conserved in a human hepatic cell line in vitro. Combinational analysis of digital gene expression and chromatin immunoprecipitation sequencing identified activating transcription factor 3 (ATF3) to be negatively regulated by IRF2BP2 in NAFLD. Chromatin immunoprecipitation and luciferase assay substantiated the fact that IRF2BP2 is a bona fide transcription repressor of ATF3 gene expression via binding to its promoter region. Functional studies revealed that ATF3 knockdown significantly relieved IRF2BP2 knockout‐exaggerated hepatosteatosis in vitro. Conclusion IRF2BP2 is an integrative restrainer in controlling hepatic steatosis, insulin resistance, and inflammation in NAFLD through transcriptionally repressing ATF3 gene expression.

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Section: Resultssupporting

confidence: 86%

Section: Discussionmentioning

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Hepatic IRF2BP2 Mitigates Nonalcoholic Fatty Liver Disease by Directly Repressing the Transcription of ATF3

Fang

Zhang

et al. 2020

Hepatology

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Cardiolipin Synthase 1 Ameliorates NASH Through Activating Transcription Factor 3 Transcriptional Inactivation

Xiong

et al. 2020

Hepatology

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BaCKgRoUND aND aIMS: NASH is an increasingly prevalent disease that is the major cause of liver dysfunction. Previous research has indicated that adipose cardiolipin synthase 1 (CRLS1) levels are associated with insulin sensitivity; however, the precise roles of CRLS1 and underlying mechanisms involving CRLS1 in the pathological process of NASH have not been elucidated. appRoaCH aND ReSUltS: Here, we discovered that CRLS1 was significantly down-regulated in genetically obese and diet-induced mice models. In vitro studies demonstrated that overexpression of CRLS1 markedly attenuated hepatic steatosis and inflammation in hepatocytes, whereas short hairpin RNA-mediated CRLS1 knockdown aggravated these abnormalities. Moreover, high-fat diet-induced insulin resistance and hepatic steatosis were significantly exacerbated in hepatocytespecific Crls1-knockout (Crls1-HKO) mice. It is worth noting that Crls1 depletion significantly aggravated high-fat and high-cholesterol diet-induced inflammatory response and fibrosis during NASH development. RNA-sequencing analysis systematically demonstrated a prominently aggravated lipid metabolism disorder in which inflammation and fibrosis resulted from Crls1 deficiency. Mechanically, activating transcription factor 3 (ATF3) was identified as the key differentially expressed gene in Crls1-HKO mice through transcriptomic analysis, and our investigation further showed that CRLS1 suppresses ATF3 expression and inhibits its activity in palmitic acid-stimulated hepatocytes, whereas ATF3 partially reverses lipid accumulation and inflammation inhibited by CRLS1 overexpression under metabolic stress. CoNClUSIoNS: In conclusion, CRLS1 ameliorates insulin resistance, hepatic steatosis, inflammation, and fibrosis during the pathological process of NASH by inhibiting the expression and activity of ATF3. (Hepatology 2020;72:1949-1967). N onalcoholic fatty liver disease (NAFLD) is the predominant cause of chronic liver disease worldwide and includes simple steatosis, NASH, and liver cirrhosis. (1) NASH usually follows simple hepatic steatosis and is characterized by lipid accumulation, insulin resistance, severe inflammation, and fibrosis in the liver. (2) As an expanding health problem, NASH has been projected to become the primary cause of liver transplantation in the next decade because of its potentially fatal pathology, leading to increased risks of cirrhosis, hepatocellular carcinoma, and liver failure. (3) Although extensive clinical and basic research has been conducted in this field, there are currently no satisfactory effective therapies for NASH. (4,5) Therefore, studying the complicated

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Preventive and therapeutic effects of natural products and herbal extracts on nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Cao

Fang

Sun

et al. 2023

Phytotherapy Research

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Nonalcoholic fatty liver disease (NAFLD) is a common condition that is prevalent in patients who consume little or no alcohol, and is characterized by excessive fat accumulation in the liver. The disease is becoming increasingly common with the rapid economic development of countries. Long‐term accumulation of excess fat can lead to NAFLD, which represents a global health problem with no effective therapeutic approach. NAFLD is a complex, multifaceted pathological process that has been the subject of extensive research over the past few decades. Herbal medicines have gained attention as potential therapeutic agents to prevent and treat NAFLD due to their high efficacy and low risk of side effects. Our overview is based on a PubMed and Web of Science database search as of Dec 22 with the keywords: NAFLD/NASH Natural products and NAFLD/NASH Herbal extract. In this review, we evaluate the use of herbal medicines in the treatment of NAFLD. These natural resources have the potential to inform innovative drug research and the development of treatments for NAFLD in the future.

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Activating transcription factor 3 is a target molecule linking hepatic steatosis to impaired glucose homeostasis

Cited by 59 publications

References 23 publications

Hepatic IRF2BP2 Mitigates Nonalcoholic Fatty Liver Disease by Directly Repressing the Transcription of ATF3

Hepatic IRF2BP2 Mitigates Nonalcoholic Fatty Liver Disease by Directly Repressing the Transcription of ATF3

Cardiolipin Synthase 1 Ameliorates NASH Through Activating Transcription Factor 3 Transcriptional Inactivation

Preventive and therapeutic effects of natural products and herbal extracts on nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

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