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Systems genetics identifies a co-regulated module of liver microRNAs associated with plasma LDL cholesterol in murine diet-induced dyslipidemia.

ABSTRACT: Chronically altered levels of circulating lipids, termed dyslipidemia, is a significant risk factor for a number of metabolic and cardiovascular morbidities. MicroRNAs (miRNAs) have emerged as important regulators of lipid balance, have been implicated in dyslipidemia, and have been proposed as candidate therapeutic targets in lipid-related disorders including atherosclerosis. A major limitation of most murine studies of miRNAs in lipid metabolic disorders is that they have been performed in just one (or very few) inbred strains, such as C57BL/6. Moreover, although individual miRNAs have been associated with lipid phenotypes, it is well understood that miRNAs likely work together in functional modules. To address these limitations, we implemented a systems genetics strategy using the Diversity Outbred (DO) mouse population. Specifically, we performed gene and miRNA expression profiling in the livers from ~300 genetically distinct DO mice after 18 wk on either a high-fat/high-cholesterol diet or a high-protein diet. Large-scale correlative analysis of these data with a wide range of cardio-metabolic end points revealed a co-regulated module of miRNAs significantly associated with circulating low-density lipoprotein cholesterol (LDL-C) levels. The hubs of this module were identified as miR-199a, miR-181b, miR-27a, miR-21_-_1, and miR-24. In sum, we demonstrate that a high-fat/high-cholesterol diet robustly rewires the miRNA regulatory network, and we identify a small group of co-regulated miRNAs that may exert coordinated effects to control circulating LDL-C.

SUBMITTER: Coffey AR

PROVIDER: S-EPMC5792136 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Systems genetics identifies a co-regulated module of liver microRNAs associated with plasma LDL cholesterol in murine diet-induced dyslipidemia.

Coffey Alisha R AR Smallwood Tangi L TL Albright Jody J Hua Kunjie K Kanke Matt M Pomp Daniel D Bennett Brian J BJ Sethupathy Praveen P

Physiological genomics 20170915 11

Chronically altered levels of circulating lipids, termed dyslipidemia, is a significant risk factor for a number of metabolic and cardiovascular morbidities. MicroRNAs (miRNAs) have emerged as important regulators of lipid balance, have been implicated in dyslipidemia, and have been proposed as candidate therapeutic targets in lipid-related disorders including atherosclerosis. A major limitation of most murine studies of miRNAs in lipid metabolic disorders is that they have been performed in jus ...[more]

PMID: 28916633

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Project description:Background & aimsInherited abnormalities in apolipoprotein E (ApoE) or low-density lipoprotein receptor (LDLR) function result in early onset cardiovascular disease and death. Currently, the only curative therapy available is liver transplantation. Hepatocyte transplantation is a potential alternative; however, physiological levels of hepatocyte engraftment and repopulation require transplanted cells to have a competitive proliferative advantage of over host hepatocytes. Herein, we aimed to test the efficacy and safety of a novel preparative regimen for hepatocyte transplantation.MethodsHerein, we used an ApoE-deficient mouse model to test the efficacy of a new regimen for hepatocyte transplantation. We used image-guided external-beam hepatic irradiation targeting the median and right lobes of the liver to enhance cell transplant engraftment. This was combined with administration of the hepatic mitogen GC-1, a thyroid hormone receptor-β agonist mimetic, which was used to promote repopulation.ResultsThe non-invasive preparative regimen of hepatic irradiation and GC-1 was well-tolerated in ApoE-/- mice. This regimen led to robust liver repopulation by transplanted hepatocytes, which was associated with significant reductions in serum cholesterol levels after transplantation. Additionally, in mice receiving this regimen, ApoE was detected in the circulation 4 weeks after treatment and did not induce an immunological response. Importantly, the normalization of serum cholesterol prevented the formation of atherosclerotic plaques in this model.ConclusionsSignificant hepatic repopulation and the cure of dyslipidemia in this model, using a novel and well-tolerated preparative regimen, demonstrate the clinical potential of applying this method to the treatment of inherited metabolic diseases of the liver.Lay summaryHepatocyte transplantation is a promising alternative to liver transplantation for the treatment of liver diseases. However, it is inefficient, as restricted growth of transplanted cells in the liver limits its therapeutic benefits. Preparative treatments improve the efficiency of this procedure, but no clinically-feasible options are currently available. In this study we develop a novel well-tolerated preparative treatment to improve growth of cells in the liver and then demonstrate that this treatment completely cures an inherited lipid disorder in a mouse model.

Project description:Diabetes is a major risk factor for atherosclerotic cardiovascular disease (ASCVD) in which dyslipidaemia plays a crucial role. Statins are first line therapy for primary and secondary prevention of ASCVD; however, adverse events include reversible musculoskeletal and liver side effects in addition to a diabetogenic association. In this short review, we provide a succinct narrative of the future role and current trial data of a novel first-in-class molecule, bempedoic acid. The authors provide their expert insight with a focus on Phase III randomised controlled trials (RCT) of bempedoic acid. Bempedoic acid was approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in February and March 2020, respectively, and is a novel molecule which inhibits cholesterol biosynthesis in the same mechanistic pathway as statins. It is a first-in-class small molecule, delivered as a prodrug and administered as an oral, once-daily dose that decreases low-density lipoprotein cholesterol (LDL-C) levels. Phase II and III RCTs have demonstrated efficacy with adequate safety data as mono- or combination therapy with statins and ezetimibe. Bempedoic acid is hepatically converted to the active drug with a lack of activation in skeletal muscle. Due to this novel mechanism, musculoskeletal-related adverse events exhibit a lower prevalence providing an alternative pharmacotherapy in statin-intolerant patients. Bempedoic acid may be used as an adjunct to diet and maximally tolerated statin therapy or in statin-intolerant patients for the treatment of dyslipidaemia. The recent National Institute of Health and Care Excellence (NICE) (UK) technology appraisal guidance [TA694] published in April 2021 recommended bempedoic acid with ezetimibe as a treatment option for primary hypercholesterolaemia or mixed dyslipidaemia if statins are not tolerated or contraindicated and if there is inadequate control of LDL-C with ezetimibe alone. Additionally, outcomes trials evaluating 'hard' endpoints in statin-intolerant patients or those with ASCVD are currently underway.

Project description:RationalePlasma low-density lipoprotein cholesterol (plasma LDL-C), vascular endothelial cells and peripheral blood mononuclear cells (PBMCs), particularly monocytes, play key roles in initiating atherosclerosis, the primary cause of cardiovascular disease (CVD). Although the mechanisms underlying development of atherosclerosis are not well understood, LDL-C is known to influence expression of endothelial microRNAs (miRNAs) and gene-targets of miRNAs to promote cell senescence. However, the impact of LDL-C on expression of PBMC miRNAs and miRNA targeted genes in response to an atherogenic diet is not known. In this study, we used unbiased methods to identify coordinately responsive PBMC miRNA- gene networks that differ between low and high LDL-C baboons when fed a high-cholesterol, high-fat (HCHF) diet.Methods and resultsUsing RNA Seq, we quantified PBMC mRNAs and miRNAs from half-sib baboons discordant for LDL-C plasma concentrations (low LDL-C, n = 3; high LDL-C, n = 3) before and after a 7-week HCHF diet challenge. For low LDL-C baboons, 626 genes exhibited significant change in expression (255 down-regulated, 371 up-regulated) in response to the HCHF diet, and for high LDL-C baboons 379 genes exhibited significant change in expression (162 down-regulated, 217 up-regulated) in response to the HCHF diet. We identified 494 miRNAs identical to human miRNAs and 47 novel miRNAs. Fifty miRNAs were differentially expressed in low LDL-C baboons (21 up- and 29 down-regulated) and 20 in high LDL-C baboons (11 up- and 9 down-regulated) in response to the HCHF diet. Among the differentially expressed miRNAs were miR-221/222 and miR-34a-3p, which were down-regulated, and miR-148a/b-5p, which was up-regulated. In addition, gene-targets of these miRNAs, VEGFA, MAML3, SPARC, and DMGDH, were inversely expressed and are central hub genes in networks and signaling pathways that differ between low and high LDL-C baboon HCHF diet response.ConclusionsWe have identified coordinately regulated HCHF diet-responsive PBMC miRNA-gene networks that differ between baboons discordant for LDL-C concentrations. Our findings provide potential insights into molecular mechanisms underlying initiation of atherosclerosis where LDL-C concentrations influence expression of specific miRNAs, which in turn regulate expression of genes that play roles in initiation of lesions.

Dataset Information

Systems genetics identifies a co-regulated module of liver microRNAs associated with plasma LDL cholesterol in murine diet-induced dyslipidemia.

Publications

Systems genetics identifies a co-regulated module of liver microRNAs associated with plasma LDL cholesterol in murine diet-induced dyslipidemia.

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