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Lysine tRNA fragments and miR-194-5p co-regulate hepatic steatosis via β-Klotho and Perilipin 2 (small RNA II)

ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) involves hepatic accumulation of intracellular lipid droplets via incompletely understood processes. Here, we report distinct and cooperative NAFLD roles of LysTTT-5’tRF transfer RNA fragments and microRNA miR-194-5p. Unlike lean animals, dietary-induced NAFLD mice showed concurrent hepatic decrease of both LysTTT-5’tRF and miR-194-5p levels, which were restored following miR-132 antisense oligonucleotide treatment which suppresses hepatic steatosis. Moreover, exposing human-derived Hep G2 cells to oleic acid for 7 days co-suppressed miR-194-5p and LysTTT-5’tRF levels while increasing lipid accumulation. Importantly, transfecting fattened cells with a synthetic LysTTT-5’tRF mimic elevated mRNA levels of the metabolic regulator β-Klotho while decreasing triglyceride amounts by 30% within 24 hours. In contradistinction, antisense suppression of miR-194-5p induced accumulation of its novel target, the NAFLD-implicated lipid droplet-coating PLIN2 protein. Further, two out of 15 steatosis-alleviating screened drug-repurposing compounds, Danazol and Latanoprost, elevated miR-194-5p or LysTTT-5’tRF levels. The different yet complementary roles of miR-194-5p and LysTTT-5’tRF offer new insights into the complex roles of small non-coding RNAs and the multiple pathways involved in NAFLD pathogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE248319 | GEO | 2024/01/31

REPOSITORIES: GEO

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Lysine tRNA fragments and miR-194-5p co-regulate hepatic steatosis via β-Klotho and Perilipin 2 (RNA)

Project description:Non-alcoholic fatty liver disease (NAFLD) involves hepatic accumulation of intracellular lipid droplets via incompletely understood processes. Here, we report distinct and cooperative NAFLD roles of LysTTT-5’tRF transfer RNA fragments and microRNA miR-194-5p. Unlike lean animals, dietary-induced NAFLD mice showed concurrent hepatic decrease of both LysTTT-5’tRF and miR-194-5p levels, which were restored following miR-132 antisense oligonucleotide treatment which suppresses hepatic steatosis. Moreover, exposing human-derived Hep G2 cells to oleic acid for 7 days co-suppressed miR-194-5p and LysTTT-5’tRF levels while increasing lipid accumulation. Importantly, transfecting fattened cells with a synthetic LysTTT-5’tRF mimic elevated mRNA levels of the metabolic regulator β-Klotho while decreasing triglyceride amounts by 30% within 24 hours. In contradistinction, antisense suppression of miR-194-5p induced accumulation of its novel target, the NAFLD-implicated lipid droplet-coating PLIN2 protein. Further, two out of 15 steatosis-alleviating screened drug-repurposing compounds, Danazol and Latanoprost, elevated miR-194-5p or LysTTT-5’tRF levels. The different yet complementary roles of miR-194-5p and LysTTT-5’tRF offer new insights into the complex roles of small non-coding RNAs and the multiple pathways involved in NAFLD pathogenesis.

2024-01-31 | GSE248320 | GEO

Lysine tRNA fragments and miR-194-5p co-regulate hepatic steatosis via β-Klotho and Perilipin 2 (small RNA I)

2024-01-31 | GSE248317 | GEO

Targeting a phospho-STAT3-miRNAs pathway improves vesicular hepatic steatosis in an in vitro model

Project description:Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease. Although genetic predisposition and epigenetic factors contribute to the development of NAFLD, our understanding of the molecular mechanism involved in the pathogenesis of the disease is still emerging. Here we investigated a possible role of a microRNAs-STAT3 pathway in the induction of hepatic steatosis. Differentiated HepaRG cells (dHepaRG) treated with the fatty acid sodium oleate recapitulated features of liver vesicular steatosis and activated a cell-autonomous inflammatory response, inducing STAT3-Tyrosine-phosphorylation. With a genome-wide approach (Chromatin Immunoprecipitation Sequencing), many phospho-STAT3 binding sites were identified in fatty dHepaRG and several STAT3 and/or NAFLD-regulated microRNAs showed increased expression levels, including miR-21. Innovative CARS (Coherent Anti-Stokes Raman Scattering) microscopy revealed that chemical inhibition of STAT3 activity decreased lipid accumulation and deregulated STAT3-responsive microRNAs, including miR-21, in lipid overloaded dHepaRG cells. We were able to show in vivo that reducing phospho-STAT3-miR-21 levels in C57/BL6 mice liver, by long-term treatment with metformin, protected mice from aging dependent hepatic vesicular steatosis. Our results identified a microRNAs-phosphoSTAT3 pathway involved in the development of hepatic steatosis, which may represent a molecular marker for both diagnosis and therapeutic targeting.

2018-09-25 | GSE89157 | GEO

Increased serum miR-193a-5p during non-alcoholic fatty liver disease progression: diagnostic and mechanistic relevance

Project description:Background & Aims: Serum microRNAs (miRNAs) levels are known to change in non-alcoholic fatty liver disease (NAFLD) and may serve as useful biomarkers. This study aimed to profile miRNAs comprehensively at all NAFLD stages. Methods:We profiled 2,083 serum miRNAs in a discovery cohort (183 NAFLD cases representing the complete NAFLD spectrum and 10 population controls). MiRNA libraries generated by HTG EdgeSeq were sequenced by Illumina NextSeq. Selected serum miRNAs were profiled in 372 additional NAFLD cases and 15 population controls by quantitative reverse transcriptase-polymerase chain reaction. Results: Levels of 275 miRNAs differed between cases and population controls. Fewer differences were seen within individual NAFLD stages but miR-193a-5p consistently the showed increased levels in all comparisons. Relative to NAFL/NASH with mild fibrosis (stage 0/1), three miRNAs (miR-193a-5p, miR-378d and miR378d) were increased in cases with NASH and clinically significant fibrosis (stage 2-4), seven (miR193a-5p, miR-378d, miR-378e, miR-320b, c, d & e) increased in cases with NAFLD Activity Score (NAS) 5-8 compared with lower NAS, and three (miR-193a-5p, miR-378d, miR-378e) increased but one (miR-19b-3p) decreased in steatosis, activity, and fibrosis "activity" (SAF-A) score 2-4 compared with lower SAF-A. The significant findings for miR-193a-5p were replicated in the additional NAFLD cohort. Studies in Hep G2 cells showed that following palmitic acid treatment, miR-193a-5p expression decreased significantly. Gene targets for miR-193a-5p were investigated in liver RNAseq data for a case subgroup (n=80); liver GPX8 levels correlated positively with serum miR-193a-5p. Conclusions: Serum miR-193a-5p levels correlate strongly with NAFLD activity grade and fibrosis stage. MiR-193a-5p may have a role in the hepatic response to oxidative stress and is a potential clinically tractable circulating biomarker for progressive NAFLD.

2022-01-31 | GSE185062 | GEO

Hepatic miR20b promotes nonalcholic fatty liver diseases by targeting PPARα

Project description:Nuclear receptors (NRs) play a crucial role in non-alcoholic fatty liver disease (NAFLD) and have been widely studied(Tran et al. 2018). However, the underlying mechanisms of NR regulation remain largely unclear. Here, we show that miR-20b plays a key role in modulating PPARα, a master regulator of nutrient metabolism and energy homeostasis in the pathogenesis of fatty liver(Wahli et al. 1995; Dongiovanni and Valenti 2013). Using network analysis and RNA-seq to determine the correlation between NRs and microRNA in NAFLD patients, we revealed that miR-20b directly targets PPARα. The expression of miR-20b was remarkably upregulated in free fatty acid (FA)-treated hepatocytes and the livers of both obesity-induced mice and NAFLD patients. Overexpression of miR-20b dramatically increased hepatic lipid accumulation and plasma triglyceride levels. Furthermore, miR-20b significantly reduced fatty acid oxidation and mitochondrial biogenesis by directly targeting PPARα. Fenofibrate, a specific agonist of PPARα, lost its ability to ameliorate hepatic steatosis in miR-20b-introduced mice. Finally, inhibition of miR-20b dramatically increased FA oxidation and uptake, resulting in improved insulin sensitivity and a decrease in NAFLD progression. Taken together, these results demonstrate that the novel miR-20b directly targets PPARα, plays a significant role in hepatic lipid metabolism, and presents an opportunity for the development of novel therapeutics for NAFLD.

2021-03-09 | GSE168484 | GEO

Expression data from liver of Cyclocarya paliurus triterpenic acids treated high-fat-diet-induced mice

Project description:Diverse targets and metabolic pathways are involved in NAFLD, which accounts for the difficulties in achieving the predominant therapeutic effects in clinical practice. Lipid accumulation is the ‘first hit’ in the development of NAFLD in liver, the dysregulation of lipid disposal can lead to hepatic steatosis. Oxidative stress is the ‘second hit’ in the pathogenesis of NAFLD. CP triterpenic acid (CPT) had an ameliorative effect on metabolic diseases, such as non-alcoholic hepatic steatosis. We used microarrays to detail the global programme of gene expression underlying cellularisation and identified distinct classes of up-regulated genes during this process.

2020-01-01 | GSE125045 | GEO

Hepatocyte Deletion of Triglyceride-Synthesis Enzyme DGAT2 Reduces Steatosis without Increasing Inflammation or Fibrosis

Project description:Non-alcoholic fatty liver disease (NAFLD) is characterized by excess lipid accumulation in hepatocytes and reprepresents a huge public health problem owing to its propensity to progress to non-alcoholic steatohepatitis (NASH), fibrosis, and liver failure. The lipids stored in hepatic steatosis are primarily triglycerides (TGs) synthesized by two acyl CoA:diacylglycerol acyltransferase (DGAT) enzymes. Either DGAT1 or DGAT2 catalyzes this reaction, and these enzymes have been suggested to differentially utilize exogenous or endogenously synthesized fatty acids, with DGAT2 being linked to storage of fatty acids from de novo lipogenesis, a process that is increased in NAFLD. However, whether DGAT2 is more responsible for lipid accumulation in NAFLD and the progression to fibrosis is currently unknown. Also, it is unresolved whether DGAT2 can be safely inhibited as a therapy for NAFLD. Here we induced NAFLD-like disease in mice by feeding a diet rich in fructose, saturated fat, and cholesterol and found that hepatocyte-specfici Dgat2 deficiency reduced expression of de novo lipogenesis genes and lowered liver TGs by ~70%. Importantly, the reduction of steatosis was not accompanied by increased inflammation or fibrosis, and insulin and glucose metabolism were unchanged. Conclusion: This study suggests that hepatic DGAT2 deficiency successfully reduced diet-induced hepatic steatosis and supports the development of DGAT2 inhibitors as a therapeutic strategy for treating NAFLD and preventing downstream consequences.

2020-05-26 | PXD013423 | Pride

Mitochondrial ACSS1-K-635 acetylation mimic knock-in mice exhibit altered lipid metabolism, hepatic cell senescence, and acute non-alcoholic fatty liver [2ndSet_analysis]

Project description:We generated an ACSS1-acetylation (Ac) mimic mouse, where lysine 635 was mutated to glutamine (K635Q). Male Acss1K635Q/K635Q mice were smaller with higher metabolic rate and blood acetate, and decreased liver/serum ATP and lactate levels. After a 48-hour fast, Acss1K635Q/K635Q mice presented hypothermia and liver aberrations, including enlargement, discoloration, lipid droplet accumulation, and microsteatosis – consistent with nonalcoholic fatty liver disease (NAFLD). RNAseq analysis suggested dysregulation of fatty acid metabolism, cellular senescence, and hepatic steatosis networks, consistent with NAFLD

2024-04-12 | GSE260582 | GEO

Mitochondrial ACSS1-K-635 acetylation mimic knock-in mice exhibit altered lipid metabolism, hepatic cell senescence, and acute non-alcoholic fatty liver [1stSet_analysis]

2024-04-12 | GSE260581 | GEO

Hepatic Lysosomal Acid Lipase Overexpression Worsens Hepatic Inflammation in Mice Fed a Western Diet

Project description:Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of lipid droplets (LD) in hepatocytes. NAFLD development and progression is associated with an increase in hepatic cholesterol and decreased autophagy and lipophagy flux. Previous studies have shown that the expression of lysosomal acid lipase (gene=LIPA, protein=LAL), which can hydrolyze both triglyceride and cholesteryl esters, is inversely correlated with the severity of NAFLD. In addition, ablation of LAL activity results in profound NAFLD. Based on this, we predicted that overexpressing LIPA in the livers of mice fed a Western diet (FPC) would prevent the development of NAFLD. As expected, mice fed the FPC diet exhibited numerous markers of NAFLD including hepatomegaly, lipid accumulation, and inflammation. Unexpectedly, LAL overexpression did not attenuate steatosis and had only minor effects on neutral lipid composition. However, LAL overexpression exacerbated inflammatory gene expression and infiltration of immune cells in mice fed the FPC diet. LAL overexpression also resulted in abnormal phagosome accumulation and lysosomal lipid accumulation depending upon the dietary treatment. Hepatic overexpression of LAL drove immune cell infiltration and inflammation and did not attenuate the development of NAFLD suggesting that targeting LAL expression is not a viable route to treat NAFLD.

2021-11-03 | GSE180377 | GEO

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