Decreased lipid metabolism but increased FA biosynthesis are coupled with changes in liver microRNAs in obese subjects with NAFLD

Latorre, Jèssica; Moreno-Navarrete, José María; Mercader, Josep M.; Sabater, Mònica; Rovira, Oscar; Gironès, Jordi; Ricart, Wifredo; Fernández-Real, José Manuel; Ortega, Francisco

doi:10.1038/ijo.2017.21

Cited by 104 publications

(88 citation statements)

References 60 publications

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“…This miRNA, belonging to the miR‐146 family along with miR‐146a, was shown to have a potential tumor‐suppressive role in HCC development and to be differentially expressed in inflammatory liver diseases . Furthermore, Xiang et al.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, autocrine IL‐6 stimulation of liver cancer progenitor cells has been described to promote malignant progression of HCC . Interestingly, the IL‐6‐induced miR‐146b‐5p was found to be up‐regulated during progression to steatosis and steatohepatitis in rats as well as in liver diseases (e.g., in obese subjects with non‐alcoholic fatty liver diseases (NAFLD) and in NASH patients). On the contrary, it has been shown that this miRNA (as well as miR‐146a‐5p) was reduced in HCC tumor tissues compared to the surrounding tissues, indicating a tumor‐suppressive role for this miRNA .…”

Section: Discussionmentioning

confidence: 99%

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Cytokine-mediated modulation of the hepatic miRNome: miR-146b-5p is an IL-6-inducible miRNA with multiple targets

Kirchmeyer

Servais

Hamdorf

et al. 2018

Journal of Leukocyte Biology

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Interleukin-6 (IL-6)-type cytokines play important roles in liver (patho-)biology. For instance, they regulate the acute phase response to inflammatory signals and are involved in hepatocarcinogenesis. Much is known about the regulation of protein-coding genes by cytokines whereas their effects on the miRNome is less well understood. We performed a microarray screen to identify microRNAs (miRNAs) in human hepatocytes which are modulated by IL-6-type cytokines. Using samples of 2 donors, 27 and 68 miRNAs (out of 1,733) were found to be differentially expressed upon stimulation with hyper-IL-6 (HIL-6) for up to 72 h, with an overlap of 15 commonly regulated miRNAs. qPCR validation revealed that miR-146b-5p was also consistently up-regulated in hepatocytes derived from 2 other donors. Interestingly, miR-146b-5p (but not miR-146a-5p) was induced by IL-6-type cytokines (HIL-6 and OSM) in non-transformed liver-derived PH5CH8 and THLE2 cells and in Huh-7 hepatoma cells, but not in HepG2 or Hep3B hepatoma cells. We did not find evidence for a differential regulation of miR-146b-5p expression by promoter methylation, also when analyzing the TCGA data set on liver cancer samples. Inducible overexpression of miR-146b-5p in PH5CH8 cells followed by RNA-Seq analysis revealed effects on multiple mRNAs, including those encoding IRAK1 and TRAF6 crucial for Toll-like receptor signaling. Indeed, LPSmediated signaling was attenuated upon overexpression of miR-146b-5p, suggesting a regulatory loop to modulate inflammatory signaling in hepatocytes. Further validation experiments suggest DNAJC6, MAGEE1, MPHOSPH6, PPP2R1B, SLC10A3, SNRNP27, and TIMM17B to be novel targets for miR-146b-5p (and miR-146a-5p). K E Y W O R D Shepatocarcinogenesis, IL-6-type cytokines, liver, microRNAs, miR-146a-5p steatohepatitis; NF B, nuclear factor kappaB; OSM, oncostatin M; PPP2R1B, protein phosphatase 2 scaffold subunit Abeta; pre-miRNA, precursor-miRNA; pri-miRNA, primary-miRNA; SRPRB, SRP receptor beta subunit; STAT, signal transducer and activator of transcription; TNF , tumor necrosis factor alpha; TRAF6, TNF receptor associated factor 6; TSS, transcription starting site This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cytokine-mediated modulation of the hepatic miRNome: miR-146b-5p is an IL-6-inducible miRNA with multiple targets

Kirchmeyer

Servais

Hamdorf

et al. 2018

Journal of Leukocyte Biology

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“…Recent studies have found that the miR-30 family play an important role in adipocyte differentiation and fat synthesis [26]. A Spanish study conducted by Latorre et al showed that patients with NAFLD and obesity had lower miR-30b-5p level in the liver compared with simple obese patients, and the expression of miR-30b-5p was decreased in hepatocytes after stimulated with fatty acid in vitro [27]. Dai et al conducted a study in 2019 showed that higher level of serum miR-30b is correlated with the higher steatosis and HOMA-IR grade [28].…”

Section: Introductionmentioning

confidence: 99%

MiR-30b-5p regulates the lipid metabolism by targeting PPARGC1A in Huh-7 cell line

Zhang

Dong

et al. 2020

Lipids Health Dis

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Background: MiRNAs are a group of multifunctional non-coding RNAs which play an important role in the various physiological processes including the development of NAFLD. Recent studies have shown that miR-30b-5p tightly associated with the abnormal lipid metabolism in patients with NAFLD, but the detailed mechanism of miR-30b-5p in the lipid metabolism was remain unclear. The aim of this study was to investigate the effect of miR-30b-5p on the lipid metabolism in hepatocellular carcinoma Huh-7 cells. Material and methods: The correlation of intracellular fat content with the expression of miR-30b-5p in Huh-7 cells and HepG2 cells was investigated by treated cells with different concentrations of FFAs. The effect of miR-30b-5p on the lipid deposition in Huh-7 cells was tested by oil red O staining and TG concentrations measurement. qRT-PCR and western blot were used to investigate the lipid metabolism-related genes PPAR-α, SREBP-1, and GULT1 in miR-30b-5p overexpressed or inhibited Huh-7 cells. Target genes of miR-30b-5p were predicted using starBase, miRDB, and TargetScan databases and verified by qRT-PCR and western blot. Results: The expression of miR-30b-5p was significant decreased in the FFAs treated Huh-7 cells and HepG2 cells. Overexpressing miR-30b-5p in Huh-7 cells decreased the number and size of lipid droplets and intracellular TG concentrations in Huh-7 cells. Expression of fatty acid oxidation related gene PPAR-α was increased and expression of lipid synthesis related gene SREBP-1 was decreased in the miR-30b-5p overexpressed Huh-7 cells. In addition, miR-30b-5p regulates the intracellular lipid metabolism by targeting PPARGC1A. Conclusions: Overexpression of miR-30b-5p could reduce the intracellular fat deposition in Huh-7 cells, and miR-30b-5p might regulate the intracellular lipid metabolism by targeting the PPARGC1A in Huh-7 cells.

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“…If a majority of miRNAs present in circulation of individuals with NAFLD originate from the liver, it would be reasonable to expect an increase in the expression of miR‐122 in hepatic parenchyma, along with a progression of NAFLD across its stages. However, in the diseased parenchyma of the livers of patients with NAFLD, intracellular levels of miR‐122 are lower than those in the livers of healthy individuals (Fig. A).…”

Section: Mir‐122: Intracellular–extracellular Seesaw Expression Paradoxmentioning

confidence: 93%

Adipose may actively delay progression of NAFLD by releasing tumor‐suppressing, anti‐fibrotic miR‐122 into circulation

2018

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Summary Nonalcoholic fatty liver disease (NAFLD) is the most common liver pathology. Here we propose tissue‐cooperative, homeostatic model of NAFLD. During early stages of NAFLD the intrahepatic production of miR‐122 falls, while the secretion of miRNA‐containing exosomes by adipose increases. Bloodstream carries exosome to the liver, where their miRNA cargo is released to regulate their intrahepatic targets. When the deterioration of adipose catches up with the failing hepatic parenchyma, the external supply of liver‐supporting miRNAs gradually tapers off, leading to the fibrotic decompensation of the liver and an increase in hepatic carcinogenesis. This model may explain paradoxical observations of the disease‐associated decrease in intrahepatic production of certain miRNAs with an increase in their levels in serum. Infusions of miR‐122 and, possibly, some other miRNAs may be efficient for preventing NAFLD‐associated hepatocellular carcinoma. The best candidates for exosome‐wrapped miRNA producer are adipose tissue‐derived mesenchymal stem cells (MSCs), known for their capacity to shed large amounts of exosomes into the media. Notably, MSC‐derived exosomes with no specific loading are already tested in patients with liver fibrosis. Carrier exosomes may be co‐manufactured along with their cargo. Exosome‐delivered miRNA cocktails may augment functioning of human organs suffering from a variety of chronic diseases.

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Decreased lipid metabolism but increased FA biosynthesis are coupled with changes in liver microRNAs in obese subjects with NAFLD

Abstract: This study confirms decreased liver glucose and lipid metabolism but increased FA biosynthesis coupled with changes in five unique miRNAs in obese patients with NAFLD.

Cited by 104 publications

References 60 publications

Cytokine-mediated modulation of the hepatic miRNome: miR-146b-5p is an IL-6-inducible miRNA with multiple targets

Cytokine-mediated modulation of the hepatic miRNome: miR-146b-5p is an IL-6-inducible miRNA with multiple targets

MiR-30b-5p regulates the lipid metabolism by targeting PPARGC1A in Huh-7 cell line

Adipose may actively delay progression of NAFLD by releasing tumor‐suppressing, anti‐fibrotic miR‐122 into circulation

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