Concurrent miR-21 suppression and FXR activation as a mechanism of improvement in nonalcoholic fatty liver disease

Mazzini, Guilherme S.; Khoraki, Jad; Browning, Matthew G.; Campos, Guilherme M.

doi:10.1038/s41419-018-0386-3

Cited by 9 publications

(7 citation statements)

References 8 publications

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“…MiR-21 has been reported to play an important role in the pathogenesis of NAFLD [ 35 ]; hence, we examined lipid metabolism in the LmiR21 liver. ORO staining of whole mount LmiR21 + Dox larvae showed more severe liver steatosis than in the controls ( Figure 2 A), indicating a higher percentage of ORO stained liver than the controls ( Figure 2 A).…”

Section: Resultsmentioning

confidence: 99%

RETRACTED: MicroRNA-21 Plays Multiple Oncometabolic Roles in the Process of NAFLD-Related Hepatocellular Carcinoma via PI3K/AKT, TGF-β, and STAT3 Signaling

Lai

Yeh

Lin

et al. 2021

Cancers

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MicroRNA-21 (miR-21) is one of the most frequently upregulated miRNAs in liver diseases such as nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC). However, mechanistic pathways that connect NAFLD and HCC remain elusive. We developed a doxycycline (Dox)-inducible transgenic zebrafish model (LmiR21) which exhibited an upregulation of miR-21 in the liver, which in turn induced the full spectrum of NAFLD, including steatosis, inflammation, fibrosis, and HCC, in the LmiR21 fish. Diethylnitrosamine (DEN) treatment led to accelerated liver tumor formation and exacerbated their aggressiveness. Moreover, prolonged miR-21 expression for up to ten months induced nonalcoholic steatohepatitis (NASH)-related HCC (NAHCC). Immunoblotting and immunostaining confirmed the presence of miR-21 regulatory proteins (i.e., PTEN, SMAD7, p-AKT, p-SMAD3, and p-STAT3) in human nonviral HCC tissues and LmiR21 models. Thus, we demonstrated that miR-21 can induce NAHCC via at least three mechanisms: First, the occurrence of hepatic steatosis increases with the decrease of ptenb, pparaa, and activation of the PI3K/AKT pathway; second, miR-21 induces hepatic inflammation (or NASH) through an increase in inflammatory gene expression via STAT3 signaling pathways, and induces liver fibrosis through hepatic stellate cell (HSC) activation and collagen deposition via TGF-β/Smad3/Smad7 signaling pathways; finally, oncogenic activation of Smad3/Stat3 signaling pathways induces HCC. Our LmiR21 models showed similar molecular pathology to the human cancer samples in terms of initiation of lipid metabolism disorder, inflammation, fibrosis and activation of the PI3K/AKT, TGF-β/SMADs and STAT3 (PTS) oncogenic signaling pathways. Our findings indicate that miR-21 plays critical roles in the mechanistic perspectives of NAHCC development via the PTS signaling networks.

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Section: Resultsmentioning

confidence: 99%

RETRACTED: MicroRNA-21 Plays Multiple Oncometabolic Roles in the Process of NAFLD-Related Hepatocellular Carcinoma via PI3K/AKT, TGF-β, and STAT3 Signaling

Lai

Yeh

Lin

et al. 2021

Cancers

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“…Strikingly, miR-21 knockout (KO) mice fed a methionine-deficient and choline-deficient (MCD) diet display markedly reduced inflammation and fibrosis, alongside improvement of steatosis, when compared with wild type animals. Similar findings were previously reported by Loyer et al 2 , except for improvements on lipid accumulation, as highlighted by Mazzini 3 . This discrepancy might result from singularities of each animal model.…”

supporting

confidence: 91%

Modulation of liver steatosis by miR-21/PPARα

Rodrigues

Castro

2018

Cell Death Discov.

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“…One such is the miR-21 that is higher in liver tissue and circulating plasma of NAFLD individuals and animal models [ 132 , 133 ]. Inhibition of the miR-21 expression alleviated steatosis by upregulation of the key regulators of lipid metabolism, such as hepatocyte nuclear factor 4 alpha ( Hnf4a ), forkhead box transcription factors ( Foxa2 and Foxo1 ), Ppara , and the signal transducer and activator of transcription 3 ( Stat3 ) [ 134 , 135 ]. Another miRNA is the miR-34a that is also higher in the liver tissue of NAFLD animal models [ 139 , 140 ].…”

Section: Alternative Diagnostic Toolsmentioning

confidence: 99%

Nonalcoholic Fatty Liver Disease (NAFLD): Pathogenesis and Noninvasive Diagnosis

et al. 2021

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The global prevalence of nonalcoholic fatty liver disease (NAFLD) or metabolic associated fatty liver disease (MAFLD), as it is now known, has gradually increased. NAFLD is a disease with a spectrum of stages ranging from simple fatty liver (steatosis) to a severe form of steatosis, nonalcoholic steatohepatitis (NASH), which could progress to irreversible liver injury (fibrosis) and organ failure, and in some cases hepatocellular carcinoma (HCC). Although a liver biopsy remains the gold standard for accurate detection of this condition, it is unsuitable for clinical screening due to a higher risk of death. There is thus an increased need to find alternative techniques or tools for accurate diagnosis. Early detection for NASH matters for patients because NASH is the marker for severe disease progression. This review summarizes the current noninvasive tools for NAFLD diagnosis and their performance. We also discussed potential and newer alternative tools for diagnosing NAFLD.

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Concurrent miR-21 suppression and FXR activation as a mechanism of improvement in nonalcoholic fatty liver disease

Cited by 9 publications

References 8 publications

RETRACTED: MicroRNA-21 Plays Multiple Oncometabolic Roles in the Process of NAFLD-Related Hepatocellular Carcinoma via PI3K/AKT, TGF-β, and STAT3 Signaling

RETRACTED: MicroRNA-21 Plays Multiple Oncometabolic Roles in the Process of NAFLD-Related Hepatocellular Carcinoma via PI3K/AKT, TGF-β, and STAT3 Signaling

Modulation of liver steatosis by miR-21/PPARα

Nonalcoholic Fatty Liver Disease (NAFLD): Pathogenesis and Noninvasive Diagnosis

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