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An In Vivo Screen Uncovers Repression of Lipoprotein Lipase by MiR-29a as a Mechanism for Lipid Flux Away From the Liver

ABSTRACT: We screened for miRNA-regulated genes in adult mouse hepatocytes by a novel AAV8-Ttr-Cre delivery system deleting a floxed Dicer1 and blocking the processing of mature miRNAs. We then used a microarray to analyze the genes at T0 (just before injection), T1 (2 weeks after injection), T2 (4 weeks after injection)

ORGANISM(S): Mus musculus

PROVIDER: GSE52526 | GEO | 2015/01/01

SECONDARY ACCESSION(S): PRJNA229156

REPOSITORIES: GEO

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A screen in mice uncovers repression of lipoprotein lipase by microRNA-29a as a mechanism for lipid distribution away from the liver.

Project description:Identification of microRNAs (miRNAs) that regulate lipid metabolism is important to advance the understanding and treatment of some of the most common human diseases. In the liver, a few key miRNAs have been reported that regulate lipid metabolism, but since many genes contribute to hepatic lipid metabolism, we hypothesized that other such miRNAs exist. To identify genes repressed by miRNAs in mature hepatocytes in vivo, we injected adult mice carrying floxed Dicer1 alleles with an adenoassociated viral vector expressing Cre recombinase specifically in hepatocytes. By inactivating Dicer in adult quiescent hepatocytes we avoided the hepatocyte injury and regeneration observed in previous mouse models of global miRNA deficiency in hepatocytes. Next, we combined gene and miRNA expression profiling to identify candidate gene/miRNA interactions involved in hepatic lipid metabolism and validated their function in vivo using antisense oligonucleotides. A candidate gene that emerged from our screen was lipoprotein lipase (Lpl), which encodes an enzyme that facilitates cellular uptake of lipids from the circulation. Unlike in energy-dependent cells like myocytes, LPL is normally repressed in adult hepatocytes. We identified miR-29a as the miRNA responsible for repressing LPL in hepatocytes, and found that decreasing hepatic miR-29a levels causes lipids to accumulate in mouse livers.Our screen suggests several new miRNAs are regulators of hepatic lipid metabolism. We show that one of these, miR-29a, contributes to physiological lipid distribution away from the liver and protects hepatocytes from steatosis. Our results, together with miR-29a's known antifibrotic effect, suggest miR-29a is a therapeutic target in fatty liver disease.

| S-EPMC4465779 | biostudies-literature

Lack of VMP1 Impairs Hepatic Lipoprotein Secretion and Promotes Nonalcoholic Steatohepatitis

Project description:The purpose of this study is to identify the differential transcriptome profiles in WT and hepatocyte deletion of VMP1 mouse livers. Floxed VMP1 mice were intravenously injected with AAV8-TBG-null or AAV8-TBG-cre for 2 weeks. Liver mRNA were extracted and performed for Nextseq analysis in triplicates.

2022-04-20 | GSE186642 | GEO

Liver fibrosis model of hepatocyte-specific FOXA2 knockout mice

Project description:Liver firbrosis model of hepatocyte-specific FOXA2 knockout mice. Adeno-associated virus AAV8-TBG-Control or AAV8-TBG-Cre was injected via the tail vein of FOXA2flox/flox (FOXA2f/f) mice 2 weeks prior to CCl4 administration. Hepatic fibrosis was induced by injection of CCl4 twice per week for 4 weeks.

2017-04-04 | GSE97344 | GEO

Analysis of the role of Mcu in the regenerating mouse liver after partial hepatectomy

Project description:In this study, we analyzed global liver gene expression in MCU knock-down (KD) mice. MCUloxp/loxp male mice were treated with an AAV8-Cre under the control of a hepatocyte specific promoter (TBG) to generate liver-specific MCU KD mice. AAV8-TBG-Null treated littermates were used as controls. Knockdown was verified 3 weeks after injection by protein and mRNA (80%). 5 weeks after injection mice were subjected to 70% partial hepatectomy and liver semples were collected 30h after the sugery. Mouse Clariom S (Affymetrix, Santa Clara, CA) arrays were used to obtain global gene expression data from pooled liver samples (pools of 4 biological replicates per array).

2020-01-01 | GSE137891 | GEO

A truncated reverse transcriptase enhances prime editing by split AAV vectors

Project description:To investigate if the truncated PE can be dilivered by dual AAV8 vectors for in vivo prime editing. We injected the dual AAV8 into 10-week-old C57BL/6J mice . Livers were isolated 4 weeks after injection and next generation sequencing showed an average of 1.4% and 5.4% precise prime editing with the low and high AAV doses, respectively (Figure 4D ). This demonstrates that PECO-Mini can be efficiently delivered by dual AAVs for in vivo prime editing.

2022-06-09 | GSE205532 | GEO

Analysis of the role of Micu1 in maintaining functional homeostasis in mouse liver

Project description:In this study, we analyzed global liver gene expression in MICU1 knock-down (KD) mice. To generate liver-specific MICU1 KD mice, MICU1loxp/loxp male mice were treated with an AAV8-Cre under the control of a hepatocyte specific promoter (TBG). AAV8-TBG-Null treated littermates were used as controls. Liver samples were collected 3-5 weeks after injection. Knockdown was verified by protein and mRNA (94%, 98%, respectively). Mouse Gene 2.0 ST (Affymetrix, Santa Clara, CA) arrays were used to obtain global gene expression data. Gene expression was profiled in control and in liver-specific Micu1 knockdown mice liver samples; 4 biological replicates per condition.

2016-01-10 | E-GEOD-69801 | biostudies-arrayexpress

Analysis of the role of Micu1 in maintaining functional homeostasis in mouse liver

2016-01-10 | GSE69801 | GEO

Cardiac lipoprotein lipase activity in the hypertrophied heart may be regulated by fatty acid flux.

Project description:Cardiac hypertrophy is characterised by an imbalance between lipid uptake and fatty acid β-oxidation leading to an accumulation of lipids, particularly triacylglycerol (TAG). It is unclear whether uptake mechanisms such as lipoprotein lipase (LPL) can be attenuated to diminish this uptake. Rats were cold acclimated to induce cardiac hypertrophy and increase cardiac LPL. Lipid uptake and metabolism were altered by feeding a 'Western-style' high fat diet (WSD) or feeding oxfenicine (2g/L) in the drinking water. Diastolic stiffness (increased volume change/unit pressure change) was induced in hypertrophied hearts for rats fed WSD (P<0.05) or WSD+oxfenicine (P<0.01), although absolute performance of cardiac muscle, estimated from stress-strain calculations was unchanged. Cold acclimation increased cardiac endothelial LPL (P<0.05) but this was diminished following oxfenicine. Following WSD LPL was further decreased below WSD-fed control hearts (P<0.05) with no further decrease by oxfenicine supplementation. A negative correlation was noted between plasma TAG and endothelial LPL (correlation coefficient=-0.654; P<0.001) but not cardiac TAG concentration. Transcript levels of angiopoietin-like protein-4 (ANGPTL4) were increased 6-fold by WSD (P<0.05) and increased 15-fold following WSD+oxfenicine (P<0.001). For CA-hearts fed WSD or WSD+oxfenicine ANGPTL4 mRNA levels were preserved at chow-fed levels. VLDLR protein levels were increased 10-fold (P<0.01) by CA. ANGPTL4 protein levels were increased 2-fold (P<0.05) by WSD, but restored following oxfenicine. For CA-hearts WSD increased ANGPTL4 protein levels 3-fold (P<0.01) with WSD+oxfenicine increasing ANGPTL4 protein 4-fold (P<0.01). These data suggest that endothelial LPL levels in the heart are altered to maintain FA flux and may exploit ANGPTL4.

| S-EPMC3793859 | biostudies-literature

High-density lipoprotein subpopulation profiles in lipoprotein lipase and hepatic lipase deficiency.

Project description:Background and aimsOur aim was to gain insight into the role that lipoprotein lipase (LPL) and hepatic lipase (HL) plays in HDL metabolism and to better understand LPL- and HL-deficiency states.MethodsWe examined the apolipoprotein (apo) A-I-, A-II-, A-IV-, C-I-, C-III-, and E-containing HDL subpopulation profiles, assessed by native 2-dimensional gel-electrophoresis and immunoblotting, in 6 homozygous and 11 heterozygous LPL-deficient, 6 homozygous and 4 heterozygous HL-deficient, and 50 control subjects.ResultsLPL-deficient homozygotes had marked hypertriglyceridemia and significant decreases in LDL-C, HDL-C, and apoA-I. Their apoA-I-containing HDL subpopulation profile was shifted toward small HDL particles compared to controls. HL-deficient homozygotes had moderate hypertriglyceridemia, modest increases in LDL-C and HDL-C level, but normal apoA-I concentration. HL-deficient homozygotes had a unique distribution of apoA-I-containing HDL particles. The normally apoA-I:A-II, intermediate-size (α-2 and α-3) particles were significantly decreased, while the normally apoA-I only (very large α-1, small α-4, and very small preβ-1) particles were significantly elevated. In contrast to control subjects, the very large α-1 particles of HL-deficient homozygotes were enriched in apoA-II. Homozygous LPL- and HL-deficient subjects also had abnormal distributions of apo C-I, C-III, and E in HDL particles. Values for all measured parameters in LPL- and HL-deficient heterozygotes were closer to values measured in controls than in homozygotes.ConclusionsOur data are consistent with the concept that LPL is important for the maturation of small discoidal HDL particles into large spherical HDL particles, while HL is important for HDL remodeling of very large HDL particles into intermediate-size HDL particles.

| S-EPMC5064856 | biostudies-literature

Expression data that were specifically regulated by lncRNA-HELF (ENSMUST00000147617 ) in livers of mice undergoing CCl4-induced liver fibrosis

Project description:Long non-coding RNAs (lncRNAs) are involved in numerous biological functions and pathological processes. In this study, we have identified a novel lncRNA ENSMUST00000147617, named Highly Expressed in Liver Fibrosis (lnc-HELF), which is remarkably up-regulated in mouse and human fibrotic livers. To identify the roles of lnc-HELF in liver fibrosis, we performed RNA-seq to analyze the effect of lnc-HELF deficient on CCl4-induced liver fibrosis. The mice were divided in three groups: mice treated with CCl4 in combination with injection of AAV8-NC (NC_CCl4, n=3), mice treated with CCl4 in combination with injection of AAV8-shRNA-lncHELF1# (sh1_CCl4, n=3) and mice treated with CCl4 in combination with injection of AAV8-shRNA-lncHELF2# (sh2_CCl4, n=3).

2023-10-05 | GSE182485 | GEO

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