Long‐term therapeutic silencing of miR‐33 increases circulating triglyceride levels and hepatic lipid accumulation in mice

Goedeke, Leigh; Salerno, Alessandro G.; Ramírez, Cristina M.; Guo, Liang; Allen, Ryan M.; Yin, Xiaoke; Langley, Sarah R.; Esau, Christine; Wanschel, Amarylis; Fisher, Edward A.; Suárez, Yajaira; Baldán, Ángel; Mayr, Manuel; Fernández‐Hernando, Carlos

doi:10.15252/emmm.201404046

Cited by 128 publications

(102 citation statements)

References 31 publications

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“…In fact, therapies targeted to raise HDL-cholesterol are effective in treating dyslipidemia and disease progression (Rayner et al 2010, Waksman et al 2010. Nevertheless, consistent with our findings, recent studies have shown that chronic increased HDL-cholesterol levels produced by some of these therapies, such as long-term therapeutic silencing of miR-33 in mice challenged with a high-fat diet, produced moderate hypertriglyceridemia and hepatic steatosis (Goedeke et al 2014). Altogether, these data suggest that modulation of lipases that develops with 'toxic' dyslipidemia (hypercholesterolemia, hypertriglyceridemia and high FFA) promote hepatic steatosis and NAFLD.…”

Section: Discussionsupporting

confidence: 90%

Hepatic lipase deficiency produces glucose intolerance, inflammation and hepatic steatosis

Andrés‐Blasco¹,

Herrero-Cervera²,

Vinué³

et al. 2015

Journal of Endocrinology

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Metabolic syndrome and type 2 diabetes mellitus constitute a major problem to global health, and their incidence is increasing at an alarming rate. Non-alcoholic fatty liver disease, which affects up to 90% of obese people and nearly 70% of the overweight, is commonly associated with MetS characteristics such as obesity, insulin resistance, hypertension and dyslipidemia. In the present study, we demonstrate that hepatic lipase (HL)-inactivation in mice fed with a high-fat, high-cholesterol diet produced dyslipidemia including hypercholesterolemia, hypertriglyceridemia and increased non-esterified fatty acid levels. These changes were accompanied by glucose intolerance, pancreatic and hepatic inflammation and steatosis. In addition, compared with WT mice, HL K/K mice exhibited enhanced circulating MCP1 levels, monocytosis and higher percentage of CD4CTh17C cells. Consistent with increased inflammation, livers from HL K/K mice had augmented activation of the stress SAPK/JNK-and p38-pathways compared with the activation levels of the kinases in livers from WT mice. Analysis of HL K/K and WT mice fed regular chow diet showed dyslipidemia and glucose intolerance in HL K/K mice without any other changes in inflammation or hepatic steatosis. Altogether, these results indicate that dyslipidemia induced by HL-deficiency in combination with a high-fat, high-cholesterol diet promotes hepatic steatosis and inflammation in mice which are, at least in part, mediated by the activation of the stress SAPK/JNK-and p38-pathways. Future studies are warranted to asses the viability of therapeutic strategies based on the modulation of these kinases to reduce hepatic steatosis associated to lipase dysfunction.

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Section: Discussionsupporting

confidence: 90%

Hepatic lipase deficiency produces glucose intolerance, inflammation and hepatic steatosis

Andrés‐Blasco¹,

Herrero-Cervera²,

Vinué³

et al. 2015

Journal of Endocrinology

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“…It has also been reported that long-term silencing of miR-33 resulted in an unexpected increase in circulating triglyceride levels and lipid accumulation in the liver. 65 Because our genetic KO mice were equivalent to permanent inhibition, long-term inhibition of miR-33 can cause harmful side effects. To utilize the protective effect of miR-33 inhibition, further research is necessary.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-33 Controls Adaptive Fibrotic Response in the Remodeling Heart by Preserving Lipid Raft Cholesterol

Nishiga

Horie

Kuwabara

et al. 2017

Circulation Research

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Rationale: Heart failure and atherosclerosis share the underlying mechanisms of chronic inflammation followed by fibrosis. A highly conserved microRNA (miR), miR-33, is considered as a potential therapeutic target for atherosclerosis because it regulates lipid metabolism and inflammation. However, the role of miR-33 in heart failure remains to be elucidated. Objective: To clarify the role of miR-33 involved in heart failure. Methods and Results: We first investigated the expression levels of miR-33a/b in human cardiac tissue samples with dilated cardiomyopathy. Increased expression of miR-33a was associated with improving hemodynamic parameters. To clarify the role of miR-33 in remodeling hearts, we investigated the responses to pressure overload by transverse aortic constriction in miR-33–deficient (knockout [KO]) mice. When mice were subjected to transverse aortic constriction, miR-33 expression levels were significantly upregulated in wild-type left ventricles. There was no difference in hypertrophic responses between wild-type and miR-33KO hearts, whereas cardiac fibrosis was ameliorated in miR-33KO hearts compared with wild-type hearts. Despite the ameliorated cardiac fibrosis, miR-33KO mice showed impaired systolic function after transverse aortic constriction. We also found that cardiac fibroblasts were mainly responsible for miR-33 expression in the heart. Deficiency of miR-33 impaired cardiac fibroblast proliferation, which was considered to be caused by altered lipid raft cholesterol content. Moreover, cardiac fibroblast–specific miR-33–deficient mice also showed decreased cardiac fibrosis induced by transverse aortic constriction as systemic miR-33KO mice. Conclusion: Our results demonstrate that miR-33 is involved in cardiac remodeling, and it preserves lipid raft cholesterol content in fibroblasts and maintains adaptive fibrotic responses in the remodeling heart.

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“…Indeed, numerous studies have demonstrated the efficacy of anti-miR-33 therapy for raising plasma HDL cholesterol levels and reducing the atherosclerotic plaque burden in both rodents and nonhuman primates (41,43,(56)(57)(58)(59). However, the increased risk for development of hepatic steatosis observed in some of these studies emphasizes the poten- tial for unintended effects of anti-miR-33 therapy (60,61). For this reason, understanding the role of miR-33 in other metabolic tissues, such as WAT, is of critical importance.…”

Section: Mir-33b Expression Is Induced During Differentiation Of Humamentioning

confidence: 99%

SREBP-1c/MicroRNA 33b Genomic Loci Control Adipocyte Differentiation

Price

Holtrup

Kwei

et al. 2016

Molecular and Cellular Biology

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White adipose tissue (WAT) is essential for maintaining metabolic function, especially during obesity. The intronic microRNAs miR33a and miR-33b, located within the genes encoding sterol regulatory element-binding protein 2 (SREBP-2) and SREBP-1, respectively, are transcribed in concert with their host genes and function alongside them to regulate cholesterol, fatty acid, and glucose metabolism. SREBP-1 is highly expressed in mature WAT and plays a critical role in promoting in vitro adipocyte differentiation. It is unknown whether miR-33b is induced during or involved in adipogenesis. This is in part due to loss of miR-33b in rodents, precluding in vivo assessment of the impact of miR-33b using standard mouse models. This work demonstrates that miR-33b is highly induced upon differentiation of human preadipocytes, along with SREBP-1. We further report that miR-33b is an important regulator of adipogenesis, as inhibition of miR-33b enhanced lipid droplet accumulation. Conversely, overexpression of miR-33b impaired preadipocyte proliferation and reduced lipid droplet formation and the induction of peroxisome proliferator-activated receptor ␥ (PPAR␥) target genes during differentiation. These effects may be mediated by targeting of HMGA2, cyclin-dependent kinase 6 (CDK6), and other predicted miR-33b targets. Together, these findings demonstrate a novel role of miR-33b in the regulation of adipocyte differentiation, with important implications for the development of obesity and metabolic disease.O besity is one of the largest burdens on the health care systems of developed countries and is a major risk factor in the development of insulin resistance, dyslipidemia, and hypertension, leading to a condition known as metabolic syndrome (1). However, obesity is not always associated with metabolic syndrome, as in the case of mice overexpressing adiponectin (2). On an ob/ob background, these mice have dramatically increased adipose tissue mass, but this does not promote insulin resistance, as the mice actually have improved insulin sensitivity. Alternatively, lipodystrophy, a condition caused by mutations that impair the expansion or differentiation of white adipose tissue (WAT), leads to severe forms of metabolic syndrome (3). Overall, the association between both impaired and excessive WAT accumulation and the development of metabolic syndrome emphasizes the critical role of WAT in maintaining metabolic homeostasis.Recent work has demonstrated an important role for WAT in regulating whole-body metabolism through the release of signaling molecules, such as leptin and adiponectin, which can regulate insulin sensitivity and appetite regulation in other tissues. Moreover, it has been known for some time that an inability of WAT to properly remove and store circulating lipids results in accumulation of lipids in nonadipose tissues, promoting diseases such as type II diabetes and atherosclerosis (4,5). De novo lipid biosynthesis is controlled by sterol regulatory element-binding proteins (SREBPs), which are activated in resp...

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Long‐term therapeutic silencing of miR‐33 increases circulating triglyceride levels and hepatic lipid accumulation in mice

Cited by 128 publications

References 31 publications

Hepatic lipase deficiency produces glucose intolerance, inflammation and hepatic steatosis

Hepatic lipase deficiency produces glucose intolerance, inflammation and hepatic steatosis

MicroRNA-33 Controls Adaptive Fibrotic Response in the Remodeling Heart by Preserving Lipid Raft Cholesterol

SREBP-1c/MicroRNA 33b Genomic Loci Control Adipocyte Differentiation

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