Obesity-induced miR-802 directly targets AMPK and promotes nonalcoholic steatohepatitis in mice

Sun, Hao; Seok, Sunmi; Jung, Ho-Youl; Kemper, Byron; Kemper, Jongsook Kim

doi:10.1016/j.molmet.2022.101603

Cited by 13 publications

(14 citation statements)

References 52 publications

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“…We utilized a mouse model that had been fed the amylin liver NASH-promoting (AMLN) diet ( Hernandez et al, 2019 ; Sun et al, 2022 ; Zhao et al, 2018 ), and examined the potential impact of liver-specific downregulation of Fincor on tropifexor’s effects on NASH pathology. Cas9 mice fed the AMLN diet for 12 weeks were injected via tail veins with adenovirus expressing control sgRNA or Fincor sgRNA, respectively, and then treated daily with tropifexor (0.3 mg/kg) for 12 days ( Figure 6A ).…”

Section: Resultsmentioning

confidence: 99%

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Hammerhead-type FXR agonists induce an enhancer RNA Fincor that ameliorates nonalcoholic steatohepatitis in mice

Chen,

Wang,

Xiong

et al. 2024

eLife

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The nuclear receptor, Farnesoid X Receptor (FXR/NR1H4), is increasingly recognized as a promising drug target for metabolic diseases, including nonalcoholic steatohepatitis (NASH). Protein coding genes regulated by FXR are well known, but whether FXR also acts through regulation of expression of long non-coding RNAs (lncRNAs), which vastly outnumber protein-coding genes, remains unknown. Utilizing RNA-seq and GRO-seq analyses in mouse liver, we found that FXR induces many RNA transcripts from chromatin regions bearing enhancer features. Among these we discovered a previously unannotated liver-enriched enhancer-derived lncRNA (eRNA), termed FincoR . We further show that FincoR is specifically induced by hammerhead-type FXR agonists, including GW4064 and tropifexor. CRISPR/Cas9-mediated liver-specific knockdown of FincoR in dietary NASH mice reduced the beneficial effects of tropifexor, an FXR agonist currently in clinical trials for NASH and primary biliary cholangitis (PBC), indicating that that amelioration of liver fibrosis and inflammation in NASH treatment by tropifexor is mediated in part by FincoR. Overall, our results indicate that pharmacological activation of FXR by hammerhead-type agonists induces a novel eRNA, FincoR , ameliorating NASH in mice. FincoR may represent a new drug target for combating metabolic disorders, including NASH.

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Section: Resultsmentioning

confidence: 99%

“…Total liver lysates were prepared as described before ( Sun et al, 2022 ). Antibodies for immunoblotting for β-ACTIN (#4970) were purchased from Cell Signaling Technology.…”

Section: Methodsmentioning

confidence: 99%

Hammerhead-type FXR agonists induce an enhancer RNA Fincor that ameliorates nonalcoholic steatohepatitis in mice

Chen,

Wang,

Xiong

et al. 2024

eLife

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“…We adopted a mouse model that had been fed the Amylin Liver NASH-promoting (AMLN) diet (Zhao et al, 2018; Hernandez et al, 2019; Sun et al, 2022) , and examined the effects of liver-specific downregulation of FincoR in potentially impacting tropifexor effects on NASH pathology. Cas9 mice fed AMLN diet for 12 weeks were injected via tail veins with adenovirus expressing control sgRNA or FincoR sgRNA, respectively, and then treated daily with tropifexor (0.3 mg/kg) for 12 days ( Figure 6A ).…”

Section: Resultsmentioning

confidence: 99%

Hammerhead-type FXR agonists induce an eRNA FincoR that ameliorates nonalcoholic steatohepatitis in mice

Chen,

Wang,

Xiong

et al. 2023

Preprint

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The nuclear receptor, Farnesoid X Receptor (FXR/NR1H4), is increasingly recognized as a promising drug target for metabolic diseases, including nonalcoholic steatohepatitis (NASH). Protein coding genes regulated by FXR are well known, but whether FXR also acts through regulation of expression of long non-coding RNAs (lncRNAs), which vastly outnumber protein-coding genes, remains unknown. Utilizing RNA-seq and GRO-seq analyses in mouse liver, we found that FXR induces many RNA transcripts from chromatin regions bearing enhancer features. Among these we discovered a previously unannotated liver-enriched enhancer-derived lncRNA (eRNA), termedFincoR. We further show thatFincoRis specifically induced by hammerhead-type FXR agonists, including GW4064 and tropifexor. CRISPR/Cas9-mediated liver-specific knockdown ofFincoRin dietary NASH mice reduced the beneficial effects of tropifexor, an FXR agonist currently in clinical trials for NASH and primary biliary cholangitis (PBC), indicating that that amelioration of liver fibrosis and inflammation in NASH treatment by tropifexor is mediated in part by FincoR. Overall, our results indicate that pharmacological activation of FXR by hammerhead-type agonists induces a novel eRNA,FincoR, ameliorating NASH in mice.FincoRmay represent a new drug target for combating metabolic disorders, including NASH.

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“…Inhibition of AMPK leads to high lipid accumulation in the liver. MiR-802 targets the AMPK gene and decreases its hepatic expression ( 60 ). Furthermore, the hepatic overexpression of miR-802 increased G6Pase levels by targeting Hnf1b ( 61 ).…”

Section: The Role Of Other Downstream Signaling Molecules On Selectiv...mentioning

confidence: 99%

Potential role of microRNAs in selective hepatic insulin resistance: From paradox to the paradigm

et al. 2022

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The paradoxical action of insulin on hepatic glucose metabolism and lipid metabolism in the insulin-resistant state has been of much research interest in recent years. Generally, insulin resistance would promote hepatic gluconeogenesis and demote hepatic de novo lipogenesis. The underlying major drivers of these mechanisms were insulin-dependent, via FOXO-1-mediated gluconeogenesis and SREBP1c-mediated lipogenesis. However, insulin-resistant mouse models have shown high glucose levels as well as excess lipid accumulation. As suggested, the inert insulin resistance causes the activation of the FOXO-1 pathway promoting gluconeogenesis. However, it does not affect the SREBP1c pathway; therefore, cells continue de novo lipogenesis. Many hypotheses were suggested for this paradoxical action occurring in insulin-resistant rodent models. A “downstream branch point” in the insulin-mediated pathway was suggested to act differentially on the FOXO-1 and SREBP1c pathways. MicroRNAs have been widely studied for their action of pathway mediation via suppressing the intermediate protein expressions. Many in vitro studies have postulated the roles of hepato-specific expressions of miRNAs on insulin cascade. Thus, miRNA would play a pivotal role in selective hepatic insulin resistance. As observed, there were confirmations and contradictions between the outcomes of gene knockout studies conducted on selective hepatic insulin resistance and hepato-specific miRNA expression studies. Furthermore, these studies had evaluated only the effect of miRNAs on glucose metabolism and few on hepatic de novo lipogenesis, limiting the ability to conclude their role in selective hepatic insulin resistance. Future studies conducted on the role of miRNAs on selective hepatic insulin resistance warrant the understanding of this paradoxical action of insulin.

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Obesity-induced miR-802 directly targets AMPK and promotes nonalcoholic steatohepatitis in mice

Cited by 13 publications

References 52 publications

Hammerhead-type FXR agonists induce an enhancer RNA Fincor that ameliorates nonalcoholic steatohepatitis in mice

Hammerhead-type FXR agonists induce an enhancer RNA Fincor that ameliorates nonalcoholic steatohepatitis in mice

Hammerhead-type FXR agonists induce an eRNA FincoR that ameliorates nonalcoholic steatohepatitis in mice

Potential role of microRNAs in selective hepatic insulin resistance: From paradox to the paradigm

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