The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis

Bala, Shashi; Csák, Tímea; Saha, Banishree; Zatsiorsky, James; Kodys, Karen; Catalano, Donna; Satishchandran, Abhishek; Szabó, Gyöngyi

doi:10.1016/j.jhep.2016.01.035

Cited by 252 publications

(290 citation statements)

References 35 publications

(76 reference statements)

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“…Therefore, to examine the therapeutic potential of MIR122 models more akin to clinical liver disease we sought a more aggressive model of ALD, by combining alcohol and carbon tetrachloride (CCl4) to induce fibrosis 20,21,22 . Briefly, mice were fed with increasing alcohol concentrations of LDC diet over 8 weeks and either CCl4 or Corn Oil i.p.…”

Section: Resultsmentioning

confidence: 99%

MicroRNA 122, Regulated by GRLH2, Protects Livers of Mice and Patients From Ethanol-Induced Liver Disease

et al. 2018

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Background & Aims Chronic, excessive alcohol consumption leads to alcoholic liver disease (ALD) characterized by steatosis, inflammation, and eventually cirrhosis. The hepatocyte specific microRNA 122 (MIR122) regulates hepatocyte differentiation and metabolism. We investigated whether an alcohol-induced decrease in level of MIR122 contributes to development of ALD. Methods We obtained liver samples from 12 patients with ALD and cirrhosis and 9 healthy individuals (controls) and analyzed them by histology and immunohistochemistry. C57Bl/6 mice were placed on a Lieber-DeCarli liquid diet, in which they were fed ethanol for 8 weeks, as a model of ALD, or a control diet. These mice were also given injections of CCl4, to increase liver fibrosis, for 8 weeks. On day 28, mice with ethanol-induced liver disease and advanced fibrosis, and controls, were given injections of recombinant adeno-associated virus 8 vector that expressed the primary miR-122 transcript (pri-MIR122, to overexpress MIR122 in hepatocytes) or vector (control). Two weeks before ethanol feeding, some mice were given injections of a vector that expressed an anti-MIR122, to knock down its expression. Serum and liver tissues were collected; hepatocytes and liver mononuclear cells were analyzed by histology, immunoblots, and confocal microscopy. We performed in silico analyses to identify targets of MIR122 and chromatin immunoprecipitation quantitative PCR analyses in Huh-7 cells. Results Levels of MIR122 were decreased in liver samples from patients with ALD and mice on the Lieber-DeCarli diet, compared with controls. Transgenic expression of MIR122 in hepatocytes of mice with ethanol-induced liver disease and advanced fibrosis significantly reduced serum levels of alanine aminotransferase (ALT) and liver steatosis and fibrosis, compared to mice given injections of the control vector. Ethanol feeding reduced expression of pri-MIR122 by increasing expression of the spliced form of the transcription factor grainyhead like transcription factor 2 (GRHL2) in livers tissues from mice. Levels of GRHL2 were also increased in liver tissues from patients with ALD, compared with controls; increases correlated with decreases in levels of MIR122 in human liver. Mice given injections of the anti-MIR122 before ethanol feeding had increased steatosis, inflammation, and serum levels of ALT compared to mice given a control vector. Levels of hypoxia inducible factor 1 alpha (HIF1A) mRNA, a target of MIR122, were increased in liver tissues from patients and mice with ALD, compared with controls. Mice with hepatocyte-specific disruption of Hif1a developed less-severe liver injury following administration of ethanol, injection of anti-MIR122, or both. Conclusions Levels of MIR122 decrease in livers from patients with ALD and mice with ethanol-induced liver disease, compared with controls. Transcription of MIR122 is inhibited by GRHL2, which is increased in livers of mice and patients with ALD. Expression of an anti-MIR122 worsened the severity of liver damage followin...

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Section: Resultsmentioning

confidence: 99%

MicroRNA 122, Regulated by GRLH2, Protects Livers of Mice and Patients From Ethanol-Induced Liver Disease

et al. 2018

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“…MicroRNA-155, an important regulator of inflammation, has been demonstrated to play a vital role in alcohol-induced steatohepatitis and fibrosis. It was found that miR-155 knockout mice are protected from alcohol-induced steatosis and inflammation, which might be attributed to increased peroxisome proliferator-activated receptor response element (PPRE) and PPAR- α binding and decreased MCP1 production [51]. In the past, the role of oxidative stress and inflammation in the pathophysiological process of ALD was investigated individually.…”

Section: The Relationship and Interdependence Between Oxidative Stmentioning

confidence: 99%

Insights into the Role and Interdependence of Oxidative Stress and Inflammation in Liver Diseases

Hong

Tan

et al. 2016

Oxidative Medicine and Cellular Longevity

268

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The crucial roles of oxidative stress and inflammation in the development of hepatic diseases have been unraveled and emphasized for decades. From steatosis to fibrosis, cirrhosis and liver cancer, hepatic oxidative stress, and inflammation are sustained and participated in this pathological progressive process. Notably, increasing evidences showed that oxidative stress and inflammation are tightly related, which are regarded as essential partners that present simultaneously and interact with each other in various pathological conditions, creating a vicious cycle to aggravate the hepatic diseases. Clarifying the interaction of oxidative stress and inflammation is of great importance to provide new directions and targets for developing therapeutic intervention. Herein, this review is concerned with the regulation and interdependence of oxidative stress and inflammation in a variety of liver diseases. In addition to classical mediators and signaling, particular emphasis is placed upon immune suppression, a potential linkage of oxidative stress and inflammation, to provide new inspiration for the treatment of liver diseases. Furthermore, since antioxidation and anti-inflammation have been extensively attempted as the strategies for treatment of liver diseases, the application of herbal medicines and their derived compounds that protect liver from injury via regulating oxidative stress and inflammation collectively were reviewed and discussed.

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“…These processes are implicated when an excess of alcohol results in inadequate metabolism, endoplasmic reticulum stress and increased fatty acid and triglyceride synthesis, all of which lead to steatosis. The peroxisome proliferator-activated receptor α is critical for alcohol metabolism and when down-regulated or depleted, results in massive fat accumulation [6,7]. Sterol regulatory element-binding proteins (SREBP) and 5′ adenosine monophosphate-activated protein kinase (AMPK) are also implicated in ALD since they play an important role in regulating lipid metabolism and their expression is altered under alcohol consumption [8,9].…”

Section: Alcoholic Fatty Livermentioning

confidence: 99%

Key Events Participating in the Pathogenesis of Alcoholic Liver Disease

2017

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Alcoholic liver disease (ALD) is a leading cause of morbidity and mortality worldwide. It ranges from fatty liver to steatohepatitis, fibrosis, cirrhosis and hepatocellular carcinoma. The most prevalent forms of ALD are alcoholic fatty liver, alcoholic hepatitis (AH) and alcoholic cirrhosis, which frequently progress as people continue drinking. ALD refers to a number of symptoms/deficits that contribute to liver injury. These include steatosis, inflammation, fibrosis and cirrhosis, which, when taken together, sequentially or simultaneously lead to significant disease progression. The pathogenesis of ALD, influenced by host and environmental factors, is currently only partially understood. To date, lipopolysaccharide (LPS) translocation from the gut to the portal blood, aging, gender, increased infiltration and activation of neutrophils and bone marrow-derived macrophages along with alcohol plus iron metabolism, with its associated increase in reactive oxygen species (ROS), are all key events contributing to the pathogenesis of ALD. This review aims to introduce the reader to the concept of alcohol-mediated liver damage and the mechanisms driving injury.

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The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis

Cited by 252 publications

References 35 publications

MicroRNA 122, Regulated by GRLH2, Protects Livers of Mice and Patients From Ethanol-Induced Liver Disease

MicroRNA 122, Regulated by GRLH2, Protects Livers of Mice and Patients From Ethanol-Induced Liver Disease

Insights into the Role and Interdependence of Oxidative Stress and Inflammation in Liver Diseases

Key Events Participating in the Pathogenesis of Alcoholic Liver Disease

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