Dataset Information

Hepatocyte miR-33a mediates mitochondrial dysfunction and hepatosteatosis by suppressing NDUFA5.

ABSTRACT: Emerging evidence suggests that microRNAs (miRNAs) are essential for metabolic haemostasis of liver tissues. Among them, miR-33a is supposed to modulate the cholesterol export and fatty acid oxidation, but whether miR-33a involves in the process of fatty liver disease is unclear. To disclose the hypothesis, we utilized miR-33a mimic and antisense to explore their effects in primary hepatocytes or high-fat diet (HFD)-fed mice. Treatment with palmitic acid (PA) or HFD significantly increased the expression of miR-33a in hepatocytes or liver tissues. In primary hepatocytes, miR-33a mimic decreased mitochondrial function, including reduction of ATP production and oxygen consumption, whereas miR-33a inhibition protected PA-induced mitochondrial dysfunction. Interestingly, miR-33a selectively suppressed mitochondrial complex I activity and protein expression, but not other complexes. Through bioinformatics prediction, we found miR-33a directly targeted on the 3'-UTR of NDUFA5. Dual-luciferase reporter analysis further confirmed the direct suppression of miR-33a on NDUFA5 expression. More importantly, administration of miR-33a antisense could effectively restore HFD-induced mitochondrial dysfunction through up-regulation of NDUFA5 levels. Mice treated with miR-33a antisense also exhibited improved liver function and structural disorders under obese status. Taken together, miR-33a was an important mediator of hepatocyte mitochondrial function, and the therapeutic benefits implied miR-33a antisense had the potential clinical application in combating the fatty liver disease.

SUBMITTER: Nie H

PROVIDER: S-EPMC6237601 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Hepatocyte miR-33a mediates mitochondrial dysfunction and hepatosteatosis by suppressing NDUFA5.

Nie Hezhongrong H Yu Xiaohong X He Haihong H Zhou Lintao L Li Qing Q Song Chunli C Wang Damin D Ren Tingyu T Chen Zeyan Z Huang Hanlian H Dai Xiaoyan X Zhou Yiwen Y

Journal of cellular and molecular medicine 20181016 12

Emerging evidence suggests that microRNAs (miRNAs) are essential for metabolic haemostasis of liver tissues. Among them, miR-33a is supposed to modulate the cholesterol export and fatty acid oxidation, but whether miR-33a involves in the process of fatty liver disease is unclear. To disclose the hypothesis, we utilized miR-33a mimic and antisense to explore their effects in primary hepatocytes or high-fat diet (HFD)-fed mice. Treatment with palmitic acid (PA) or HFD significantly increased the e ...[more]

PMID: 30324697

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Project description:Mitochondrial dysfunction is a key contributor to septic cardiomyopathy. Although recent literature implicates dynamin related protein 1 (Drp1) and its mitochondrial adaptor fission 1 (Fis1) in the development of pathologic fission and mitochondrial failure in neurodegenerative disease, little is known about the role of Drp1/Fis1 interaction in the context of sepsis-induced cardiomyopathy. Our study tests the hypothesis that Drp1/Fis1 interaction is a major driver of sepsis-mediated pathologic fission, leading to mitochondrial dysfunction in the heart.MethodsH9C2 cardiomyocytes were treated with lipopolysaccharide (LPS) to evaluate changes in mitochondrial membrane potential, oxidative stress, cellular respiration, and mitochondrial morphology. Balb/c mice were treated with LPS, cardiac function was measured by echocardiogaphy, and mitochondrial morphology determined by electron microscopy (EM). Drp1/Fis1 interaction was inhibited by P110 to determine whether limiting mitochondrial fission can reduce LPS-induced oxidative stress and cardiac dysfunction.ResultsLPS-treated H9C2 cardiomyocytes demonstrated a decrease in mitochondrial respiration followed by an increase in mitochondrial oxidative stress and a reduction in membrane potential. Inhibition of Drp1/Fis1 interaction with P110 attenuated LPS-mediated cellular oxidative stress and preserved membrane potential. In vivo, cardiac dysfunction in LPS-treated mice was associated with increased mitochondrial fragmentation. Treatment with P110 reduced cardiac mitochondrial fragmentation, prevented decline in cardiac function, and reduced mortality.ConclusionsSepsis decreases cardiac mitochondrial respiration and membrane potential while increasing oxidative stress and inducing pathologic fission. Treatment with P110 was protective in both in vitro and in vivo models of septic cardiomyopathy, suggesting a key role of Drp1/Fis1 interaction, and a potential target to reduce its morbidity and mortality.

Dataset Information

Hepatocyte miR-33a mediates mitochondrial dysfunction and hepatosteatosis by suppressing NDUFA5.

Publications

Hepatocyte miR-33a mediates mitochondrial dysfunction and hepatosteatosis by suppressing NDUFA5.

Similar Datasets

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