Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We identified murine miR-322, orthologous to human miR-424, as a new regulator of insulin receptor, IGF-1 receptor and sirtuin 4 mRNA in vitro and in vivo in the heart and found that miR-322/424 is highly expressed in the heart of mice. C57Bl/6N mice fed 10weeks of high fat diet (HFD) presented signs of cardiomyopathy and a stable miR-322 cardiac level while cardiac function was slightly affected in 11week-old ob/ob which overexpressed miR-322. We thus hypothesized that mmu-miR-322 could be protective against cardiac consequences of hyperinsulinemia and hyperlipidemia. We overexpressed or knocked-down mmu-miR-322 using AAV9 and monitored cardiac function in wild-type C57Bl/6N mice fed a control diet (CD) or a HFD and in ob/ob mice. The fractional shortening progressively declined while the left ventricle systolic diameter increased in HFD mice infected with an AAVcontrol or with an AAVsponge (decreasing miR-322 bioavailability) but also in ob/ob mice infected with AAVsponge. Similar observations were also found in CD-fed mice infected with AAVsponge. On the contrary over-expressing miR-322 with AAVmiR-322 was efficient in protecting the heart from HFD effects in C57Bl/6N mice. This cardioprotection could be associated with the regulation of identified targets IGF1R, INSR and CD1, a decrease in insulin signaling pathway and an enrichment of genes involved in mitochondrial function and fatty acid oxidation as demonstrated by transcriptome analysis. Altogether, these results emphasize miR-322 as a new potential therapeutic target against cardiac consequences of metabolic syndrome, which represents an increasing burden in the western countries.
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PMID:miR-322 regulates insulin signaling pathway and protects against metabolic syndrome-induced cardiac dysfunction in mice. 2677 30

Atherosclerosis is a chronic inflammatory disorder that develops in response to hyperlipidaemia. Cells from both the innate and adaptive immune systems contribute to the development of atherosclerotic lesions. The role of natural killer T (NKT) cells in response to microbial pathogens and inflammatory disorders such as atherosclerosis has received increasing attention in the past 10-15 years. Endogenous self-lipid antigens and exogenous lipid antigens, including those on microorganisms can activate NKT cells. CD1d molecules on antigen-presenting cells present these lipids to the T-cell receptor on NKT cells, which results in the rapid production of cytokines and cytotoxic proteins. NKT cells can also be activated in a CD1d-independent manner. Numerous studies have shown that NKT cells can promote atherogenesis. Various NKT cell sublineages have been described, but the participation of each in atherogenesis requires further characterization. In this Review, we provide an overview of NKT cells in the immune system, discuss CD1 molecules and lipid antigen presentation, and describe the interaction of the CD1d-NKT cell network with gut microbiota and its effect in modulating the activity or levels of NKT cells, which might in turn influence atherosclerosis. Although the exact mechanisms by which NKT cells promote atherosclerosis have not been fully elucidated, several potential mechanisms are proposed.
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PMID:Natural killer T cells in atherosclerosis. 2812 28

A large proportion of human T cells are autoreactive to group 1 CD1 proteins, which include CD1a, CD1b, and CD1c. However, the physiological role of the CD1 proteins remains poorly defined. Here, we have generated a double-transgenic mouse model that expresses human CD1b and CD1c molecules (hCD1Tg) as well as a CD1b-autoreactive TCR (HJ1Tg) in the ApoE-deficient background (hCD1Tg HJ1Tg Apoe-/- mice) to determine the role of CD1-autoreactive T cells in hyperlipidemia-associated inflammatory diseases. We found that hCD1Tg HJ1Tg Apoe-/- mice spontaneously developed psoriasiform skin inflammation characterized by T cell and neutrophil infiltration and a Th17-biased cytokine response. Anti-IL-17A treatment ameliorated skin inflammation in vivo. Additionally, phospholipids and cholesterol preferentially accumulated in diseased skin and these autoantigens directly activated CD1b-autoreactive HJ1 T cells. Furthermore, hyperlipidemic serum enhanced IL-6 secretion by CD1b+ DCs and increased IL-17A production by HJ1 T cells. In psoriatic patients, the frequency of CD1b-autoreactive T cells was increased compared with that in healthy controls. Thus, this study has demonstrated the pathogenic role of CD1b-autoreactive T cells under hyperlipidemic conditions in a mouse model of spontaneous skin inflammation. As a large proportion of psoriatic patients are dyslipidemic, this finding is of clinical significance and indicates that self-lipid-reactive T cells might serve as a possible link between hyperlipidemia and psoriasis.
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PMID:CD1b-autoreactive T cells contribute to hyperlipidemia-induced skin inflammation in mice. 2846 30