Neutrophil-to-hepatocyte communication via LDLR-dependent miR-223–enriched extracellular vesicle transfer ameliorates nonalcoholic steatohepatitis

He, Yong; Rodrigues, Robim Marcelino; Wang, Xiaolin; Seo, Wonhyo; Ma, Jing; Hwang, Seonghwan; Fu, Yukui; Trojnár, Eszter; Mátyás, Csaba; Zhao, Suxian; Ren, Ruixue; Feng, Dechun; Pacher, Pál; Kunos, George; Gao, Bin

doi:10.1172/jci141513

Cited by 113 publications

(104 citation statements)

References 64 publications

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“…Some of the target genes of miR-223 (such as CXCL10 , NLRP3 , and TAZ ) induce inflammation and fibrosis in the liver and promote the progression of NAFLD. EV-derived miR-223, when taken up by hepatocytes, suppresses hepatic inflammatory and fibrogenic gene expression [ 102 ]. miR-372-3p and miR-373-3p, which downregulate adipocyte enhancer binding protein 1 (AEBP1), are reduced in patients with NASH and advanced fibrosis [ 64 ].…”

Section: Association Of the Causes Of Liver Cirrhosis And Mirnasmentioning

confidence: 99%

Diagnosis and Therapeutic Management of Liver Fibrosis by MicroRNA

Tadokoro

Morishita

Masaki

2021

IJMS

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Remarkable progress has been made in the treatment and control of hepatitis B and C viral infections. However, fundamental treatments for diseases in which liver fibrosis is a key factor, such as cirrhosis, alcoholic/nonalcoholic steatohepatitis, autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis, are still under development and remain an unmet medical need. To solve this problem, it is essential to elucidate the pathogenesis of liver fibrosis in detail from a molecular and cellular perspective and to develop targeted therapeutic agents based on this information. Recently, microRNAs (miRNAs), functional RNAs of 22 nucleotides, have been shown to be involved in the pathogenesis of liver fibrosis. In addition, extracellular vesicles called “exosomes” have been attracting attention, and research is being conducted to establish noninvasive and extremely sensitive biomarkers using miRNAs in exosomes. In this review, we summarize miRNAs directly involved in liver fibrosis, miRNAs associated with diseases leading to liver fibrosis, and miRNAs related to complications of cirrhosis. We will also discuss the efficacy of each miRNA as a biomarker of liver fibrosis and pathology, and its potential application as a therapeutic agent.

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Section: Association Of the Causes Of Liver Cirrhosis And Mirnasmentioning

confidence: 99%

Diagnosis and Therapeutic Management of Liver Fibrosis by MicroRNA

Tadokoro

Morishita

Masaki

2021

IJMS

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“…Besides the hepatocyte-released miRNAs mentioned above, exosomal miRNAs released by myeloid cells have also attracted attention as mediators of NAFLD development. miR-223 is predominantly expressed in myeloid cells and participates in inflammation regulation (Ye et al 2018), but can also be transferred to other liver cell types (e.g., hepatocytes) via exosomes (He et al 2020). Myeloid-specific deletion of the Il6ra gene in mice accelerated HFD-induced fibrosis development by lowering miR-223 levels in hepatocytes and subsequently activating fibrogenic mediators, such as transcriptional activator with PDZ-binding motif (TAZ) (Hou et al 2020).…”

Section: Nonalcoholic Fatty Liver Disease (Nafld)mentioning

confidence: 99%

Exosomal microRNAs as diagnostic and therapeutic biomarkers in non-malignant liver diseases

Hwang

Yang

2021

Arch. Pharm. Res.

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“…Of interest, in a cohort of human patients with liver cirrhosis secondary to alcohol consumption, serum PCSK9 was reduced compared to non-cirrhotic patients and was not correlated with the severity of liver disease, bilirubin, or aminotransferases, suggesting dynamic expression of PCSK9 throughout liver disease progression [100]. PCSK9 inhibition by alirocumab, a monoclonal antibody against PCSK9, upregulated hepatic LDLR expression and attenuated liver neutrophil and macrophage infiltration, hepatocellular injury, steatosis, and fibrosis in a mouse model of non-alcoholic steatohepatitis [101]. Alirocumab treatment also increased the expression of the VLDL-related gene microsomal triglyceride transfer protein (Mttp), but not several β-oxidation-related genes, suggesting that induction of LDLR following alirocumab treatment may contribute to limiting liver injury by improving VLDL synthesis [101].…”

Section: Livermentioning

confidence: 99%

“…PCSK9 inhibition by alirocumab, a monoclonal antibody against PCSK9, upregulated hepatic LDLR expression and attenuated liver neutrophil and macrophage infiltration, hepatocellular injury, steatosis, and fibrosis in a mouse model of non-alcoholic steatohepatitis [101]. Alirocumab treatment also increased the expression of the VLDL-related gene microsomal triglyceride transfer protein (Mttp), but not several β-oxidation-related genes, suggesting that induction of LDLR following alirocumab treatment may contribute to limiting liver injury by improving VLDL synthesis [101]. In human genetic studies, the PCSK9 rs11591147 loss-of-function (LOF) variant was protective against liver steatosis, nonalcoholic steatohepatitis, and fibrosis [102].…”

Section: Livermentioning

confidence: 99%

PCSK9 and the Gut-Liver-Brain Axis: A Novel Therapeutic Target for Immune Regulation in Alcohol Use Disorder

Lee

O’Connell

Pacher

et al. 2021

JCM

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Alcohol use disorder (AUD) is a chronic relapsing disorder characterized by an impaired ability to control or stop alcohol intake and is associated with organ damage including alcohol-associated liver disease (ALD) and progressive neurodegeneration. The etiology of AUD is complex, but organ injury due to chronic alcohol use can be partially attributed to systemic and local inflammation along the gut-liver-brain axis. Excessive alcohol use can result in translocation of bacterial products into circulation, increased expression of pro-inflammatory cytokines, and activation of immune cells, including macrophages and/or microglia in the liver and brain. One potential mediator of this alcohol-induced inflammation is proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 is primarily known for its regulation of plasma low-density lipoprotein cholesterol but has more recently been shown to influence inflammatory responses in the liver and brain. In rodent and post-mortem brain studies, chronic alcohol use altered methylation of the PCSK9 gene and increased expression of PCSK9 in the liver and cerebral spinal fluid. Additionally, PCSK9 inhibition in a rat model of ALD attenuated liver inflammation and steatosis. PCSK9 may play an important role in alcohol-induced pathologies along the gut-liver-brain axis and may be a novel therapeutic target for AUD-related liver and brain inflammation.

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Neutrophil-to-hepatocyte communication via LDLR-dependent miR-223–enriched extracellular vesicle transfer ameliorates nonalcoholic steatohepatitis

Cited by 113 publications

References 64 publications

Diagnosis and Therapeutic Management of Liver Fibrosis by MicroRNA

Diagnosis and Therapeutic Management of Liver Fibrosis by MicroRNA

Exosomal microRNAs as diagnostic and therapeutic biomarkers in non-malignant liver diseases

PCSK9 and the Gut-Liver-Brain Axis: A Novel Therapeutic Target for Immune Regulation in Alcohol Use Disorder

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