Effects of miR-33 Deficiency on Metabolic and Cardiovascular Diseases: Implications for Therapeutic Intervention

Ortega, Rebeca; Liu, Bo; Persaud, Shanta J.

doi:10.3390/ijms241310777

Cited by 10 publications

(4 citation statements)

References 121 publications

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“…Induction of miR-33 expression inhibits the expression of several target genes; some are involved in reverse cholesterol transport in macrophages (ATP-binding cassette transporter ABCA1 and ABCG1), while others are implicated in fatty acid metabolism such as carnitine palmitoyltransferase 1A (CPT1A), hydroxyacyl-CoA-dehydrogenase (HADHD), and carnitine O-octanoyltransferase (CROT). By inhibiting such targets, miR-33 is responsible for the increase in the size of atheroma plaques and hepatic lipid accumulation through impaired insulin response (it represses phosphorylation of IRS-2 and AKT) ( 16 ).…”

Section: Discussionmentioning

confidence: 99%

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Time for micro-RNAs in steatotic liver disease: a case–control study

Stoica,

Apostol,

Diculescu

et al. 2024

Front. Endocrinol.

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One of the challenges of modern-day living is to resist the temptation of overfeeding and sedentariness and maintain a healthy body and mind. On a favorable genetic and epigenetic background, a high-fat diet combined with lack of physical exercise constitutes the foundation for severe metabolic disturbances including steatotic liver disease. In our case–control study, we had the aim of establishing the role of selected micro-RNAs—miR-122, miR-192, miR-33a, and miR-33b—as superior biomarkers for the diagnosis and prognosis of steatotic liver in a 36-patient cohort compared to 12 healthy controls. Initial results confirmed the decline in miR-122 expression as fatty liver is progressing. However, combinations of ΔmiRs, such as ΔmiR33a_192, ΔmiR33a_122, and ΔmiR33b_122, correlate with ultrasound steatosis grade (R2 = 0.78) while others such as ΔmiR33b_122 provide a high specificity and sensitivity in fatty liver disease with an area under the curve (AUC) of 0.85. Compared to classical biomarkers, micro-RNAs can be used for both diagnostic and prognostic purposes as their diminished expression in severe cases of steatosis is associated with higher risk of emerging hepatocellular carcinoma. Manipulating micro-RNAs through agomirs or antagomirs can be the answer to the yet unsolved problem of efficient therapy in MAFLD.

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Section: Discussionmentioning

confidence: 99%

“…For several decades, we based many of our clinical decisions on classical biomarkers of liver injury with low sensibility and specificity. Animal trials all showed important deregulation of specific miRNAs in rats fed with high-fat or high-fructose diets ( 15 , 16 ).…”

Section: Literature Review and Hypotheses Developmentmentioning

confidence: 99%

Time for micro-RNAs in steatotic liver disease: a case–control study

Stoica,

Apostol,

Diculescu

et al. 2024

Front. Endocrinol.

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“…miR-483-5p targets ERK1 and positively regulates PPARγ expression and promotes adipogenesis in mouse preadipocyte 3T3-L1 cells and human adipose-derived MSCs [56,70]. miR-33 may prevent the onset of obesity [71]. Compared to control mice, miR-33-deficient mice are more likely to become obese due to increased food intake caused by an increased secretion of orexigenic hormones, such as ghrelin, or leptin resistance [66].…”

Section: Mirnas and Obesitymentioning

confidence: 99%

MicroRNAs and Nonalcoholic Steatohepatitis: A Review

Morishita,

Oura,

Tadokoro

et al. 2023

IJMS

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Non-alcoholic fatty liver disease (NAFLD) is a clinicopathologic syndrome caused by fat deposition in hepatocytes. Patients with nonalcoholic steatohepatitis (NASH), an advanced form of NAFLD with severe fibrosis, are at high risk for liver-related complications, including hepatocellular carcinoma (HCC). However, the mechanism of progression from simple fat deposition to NASH is complex, and previous reports have linked NAFLD to gut microbiota, bile acids, immunity, adipokines, oxidative stress, and genetic or epigenetic factors. NASH-related liver injury involves multiple cell types, and intercellular signaling is thought to be mediated by extracellular vesicles. MicroRNAs (miRNAs) are short, noncoding RNAs that play important roles as post-transcriptional regulators of gene expression and have been implicated in the pathogenesis of various diseases. Recently, many reports have implicated microRNAs in the pathogenesis of NALFD/NASH, suggesting that exosomal miRNAs are potential non-invasive and sensitive biomarkers and that the microRNAs involved in the mechanism of the progression of NASH may be potential therapeutic target molecules. We are interested in which miRNAs are involved in the pathogenesis of NASH and which are potential target molecules for therapy. We summarize targeted miRNAs associated with the etiology and progression of NASH and discuss each miRNA in terms of its pathophysiology, potential therapeutic applications, and efficacy as a NASH biomarker.

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“…ApoAI is known to exclusively act as a cholesterol acceptor for ABCA1 [ 14 ] and so strategies to increase ABCA1 expression within MLC may result in atheroprotection via removing intracellular cholesterol through enhanced apoAI-mediated cholesterol efflux. The microRNA miR-33a-5p is well-recognized to silence ABCA1 expression [ 15 ]. Interestingly, miR-33a-5p is capable of silencing ABCG1 expression in rodents, but not in humans, while extensive published literature implies SR-BI to not be a likely target gene for miR-33a-5p [ 16 , 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of miR-33a-5p in Macrophage-like Cells In Vitro Promotes apoAI-Mediated Cholesterol Efflux

Oladosu,

Chin,

Barksdale

et al. 2024

Pathophysiology

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Atherosclerosis is caused by cholesterol accumulation within arteries. The intima is where atherosclerotic plaque accumulates and where lipid-laden foam cells reside. Intimal foam cells comprise of both monocyte-derived macrophages and macrophage-like cells (MLC) of vascular smooth muscle cell (VSMC) origin. Foam cells can remove cholesterol via apoAI-mediated cholesterol efflux and this process is regulated by the transporter ABCA1. The microRNA miR-33a-5p is thought to be atherogenic via silencing ABCA1 which promotes cholesterol retention and data has shown inhibiting miR-33a-5p in macrophages may be atheroprotective via enhancing apoAI-mediated cholesterol efflux. However, it is not entirely elucidated whether precisely inhibiting miR-33a-5p in MLC also increases ABCA1-dependent cholesterol efflux. Therefore, the purpose of this work is to test the hypothesis that inhibition of miR-33a-5p in cultured MLC enhances apoAI-mediated cholesterol efflux. In our study, we utilized the VSMC line MOVAS cells in our experiments, and cholesterol-loaded MOVAS cells to convert this cell line into MLC. Inhibition of miR-33a-5p was accomplished by transducing cells with a lentivirus that expresses an antagomiR directed at miR-33a-5p. Expression of miR-33a-5p was analyzed by qRT-PCR, ABCA1 protein expression was assessed via immunoblotting, and apoAI-mediated cholesterol efflux was measured using cholesterol efflux assays. In our results, we demonstrated that lentiviral vector-mediated knockdown of miR-33a-5p resulted in decreasing expression of this microRNA in cultured MLC. Moreover, reduction of miR-33a-5p in cultured MLC resulted in de-repression of ABCA1 expression, which caused ABCA1 protein upregulation in cultured MLC. Additionally, this increase in ABCA1 protein expression resulted in enhancing ABCA1-dependent cholesterol efflux through increasing apoAI-mediated cholesterol efflux in cultured MLC. From these findings, we conclude that inhibiting miR-33a-5p in MLC may protect against atherosclerosis by promoting ABCA1-dependent cholesterol efflux.

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Effects of miR-33 Deficiency on Metabolic and Cardiovascular Diseases: Implications for Therapeutic Intervention

Cited by 10 publications

References 121 publications

Time for micro-RNAs in steatotic liver disease: a case–control study

Time for micro-RNAs in steatotic liver disease: a case–control study

MicroRNAs and Nonalcoholic Steatohepatitis: A Review

Inhibition of miR-33a-5p in Macrophage-like Cells In Vitro Promotes apoAI-Mediated Cholesterol Efflux

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