Analysis of mycobacterial infection-induced changes to host lipid metabolism in a zebrafish infection model reveals a conserved role for LDLR in infection susceptibility

AbstractChanges to lipid metabolism are well-characterised consequences of human tuberculosis infection but their functional relevance are not clearly elucidated in these or other host-mycobacterial systems. The zebrafish-Mycobacterium marinum infection model is used extensively to model many aspects of human-M. tuberculosis pathogenesis but has not been widely used to study the role of infection-induced lipid metabolism. We find mammalian mycobacterial infection-induced alterations in host Low Density Lipoprotein metabolism are conserved in the zebrafish model of mycobacterial pathogenesis. Depletion of LDLR, a key lipid metabolism node, decreased M. marinum burden, and corrected infection-induced altered lipid metabolism resulting in decreased LDL and reduced the rate of macrophage transformation into foam cells. Our results demonstrate a conserved role for infection-induced alterations to host lipid metabolism, and specifically the LDL-LDLR axis, across host-mycobacterial species pairings.FundingThis work was supported by the Australian National Health and Medical Research Council (APP1099912 and APP1053407 to S.H.O.); Meat and Livestock Australia (P.PSH. 0813 to A.C.P. and K. dS); the Marie Bashir Institute for Infectious Diseases and Biosecurity (grant to S.H.O., A.C.P. and K. dS); the Kenyon Family Foundation Inflammation Award (grant to S.H.O.); the University of Sydney (fellowship to S.H.O.); Consellería de Economía, Emprego e Industria (GAIN), Xunta de Galicia (grant IN607B 2016/12 to Institute of Marine Research (IIM-CSIC)).

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Adenovirus-Mediated High Expression of Resistin Causes Dyslipidemia in Mice

Endocrinology ◽

10.1210/en.2004-0985 ◽

2005 ◽

Vol 146 (1) ◽

pp. 273-279 ◽

Cited By ~ 53

Author(s):

Naoichi Sato ◽

Kunihisa Kobayashi ◽

Toyoshi Inoguchi ◽

Noriyuki Sonoda ◽

Minako Imamura ◽

...

Keyword(s):

Lipid Metabolism ◽

Phosphoenolpyruvate Carboxykinase ◽

Low Density Lipoprotein ◽

Lipoprotein Metabolism ◽

Density Lipoprotein ◽

Glucose Production ◽

Low Density ◽

Adenoviral Gene Transfer ◽

Insulin Resistant

The adipocyte-derived hormone resistin has been proposed as a possible link between obesity and insulin resistance in murine models. Many recent studies have reported physiological roles for resistin in glucose homeostasis, one of which is enhancement of glucose production from the liver by up-regulating gluconeogenic enzymes such as glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. However, its in vivo roles in lipid metabolism still remain to be clarified. In this study, we investigated the effects of resistin overexpression on insulin action and lipid metabolism in C57BL/6 mice using an adenoviral gene transfer technique. Elevated plasma resistin levels in mice treated with the resistin adenovirus (AdmRes) were confirmed by Western blotting analysis and RIAs. Fasting plasma glucose levels did not differ between AdmRes-treated mice and controls, but the basal insulin concentration was significantly elevated in AdmRes-treated mice. In AdmRes-treated mice, the glucose-lowering effect of insulin was impaired, as evaluated by insulin tolerance tests. Furthermore, total cholesterol and triglyceride concentrations were significantly higher, whereas the high-density lipoprotein cholesterol level was significantly lower. Lipoprotein analysis revealed that low-density lipoprotein was markedly increased in AdmRes-treated mice, compared with controls. In addition, in vivo Triton WR-1339 studies showed evidence of enhanced very low-density lipoprotein production in AdmRes-treated mice. The expressions of genes involved in lipoprotein metabolism, such as low-density lipoprotein receptor and apolipoprotein AI in the liver, were decreased. These results suggest that resistin overexpression induces dyslipidemia in mice, which is commonly seen in the insulin-resistant state, partially through enhanced secretion of lipoproteins.

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Analysis of mycobacterial infection-induced changes to host lipid metabolism in a zebrafish infection model reveals a conserved role for LDLR in infection susceptibility

Fish & Shellfish Immunology ◽

10.1016/j.fsi.2018.09.037 ◽

2018 ◽

Vol 83 ◽

pp. 238-242 ◽

Cited By ~ 4

Author(s):

Matt D. Johansen ◽

Elinor Hortle ◽

Joshua A. Kasparian ◽

Alejandro Romero ◽

Beatriz Novoa ◽

...

Keyword(s):

Lipid Metabolism ◽

Mycobacterial Infection ◽

Infection Model ◽

Infection Susceptibility ◽

Induced Changes ◽

Zebrafish Infection

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MicroRNAs regulating lipid metabolism in atherogenesis

Thrombosis and Haemostasis ◽

10.1160/th11-10-0694 ◽

2012 ◽

Vol 107 (04) ◽

pp. 642-647 ◽

Cited By ~ 56

Author(s):

Katey J. Rayner ◽

Carlos Fernández-Hernando ◽

Kathryn J. Moore

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

Metabolic Diseases ◽

Low Density Lipoprotein ◽

Lipoprotein Metabolism ◽

Density Lipoprotein ◽

Acid Synthesis ◽

Acid Oxidation ◽

Element Binding Protein ◽

Plasma High Density

SummaryMicroRNAs have emerged as important post-transcriptional regulators of lipid metabolism, and represent a new class of targets for therapeutic intervention. Recently, microRNA-33a and b (miR-33a/b) were discovered as key regulators of metabolic programs including cholesterol and fatty acid homeostasis. These intronic microRNAs are embedded in the sterol response element binding protein genes, SREBF2 and SREBF1, which code for transcription factors that coordinate cholesterol and fatty acid synthesis. By repressing a variety of genes involved in cholesterol export and fatty acid oxidation, including ABCA1, CROT, CPT1, HADHB and PRKAA1, miR-33a/b act in concert with their host genes to boost cellular sterol levels. Recent work in animal models has shown that inhibition of these small non-coding RNAs has potent effects on lipoprotein metabolism, including increasing plasma high-density lipo-protein (HDL) and reducing very low density lipoprotein (VLDL) triglyce-rides. Furthermore, other microRNAs are being discovered that also target the ABCA1 pathway, including miR-758, suggesting that miRNAs may work cooperatively to regulate this pathway. These exciting findings support the development of microRNA antagonists as potential therapeutics for the treatment of dyslipidaemia, atherosclerosis and related metabolic diseases.

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MicroRNAs in Lipid Metabolism and Atherosclerosis

The Indonesian Biomedical Journal ◽

10.18585/inabj.v6i1.39 ◽

2014 ◽

Vol 6 (1) ◽

pp. 3 ◽

Cited By ~ 1

Author(s):

Anna Meiliana ◽

Andi Wijaya

Keyword(s):

Lipid Metabolism ◽

Low Density Lipoprotein ◽

Lipoprotein Metabolism ◽

Density Lipoprotein ◽

Biological Pathways ◽

Oxidized Low Density Lipoprotein ◽

Unique Approach ◽

Endothelial Integrity ◽

Potential Therapeutics

BACKGROUND: MicroRNAs (miRNA) are mediators of post-transcriptional gene expression that likely regulate most biological pathways and networks. The study of miRNAs is a rapidly emerging field; recent findings have revealed a significant role for miRNAs in atherosclerosis and lipoprotein metabolism.CONTENT: Results from recent studies demonstrated a role for miRNAs in endothelial integrity, macrophage inflammatory response to oxidized low-density lipoprotein, vascular smooth muscle cell proliferation and cholesterol synthesis. These mechanisms are all vital to the initiation and proliferation of atherosclerosis and cardiovascular disease. The importance of miRNAs has recently been recognized in cardiovascular sciences and miRNAs will likely become an integral part of our fundamental comprehension of atherosclerosis and lipoprotein metabolism. The extensive impact of miRNA mediated gene regulation and the relative ease of in vivo applicable modifications highlight the enormous potential of miRNA-based therapeutics in cardiovascular diseases.SUMMARY: miRNA studies in the field of lipid metabolism and atherosclerosis are in their infancy, and thus there is tremendous opportunity for discovery in this understudied area. The ability to target miRNAs in vivo through delivery of miRNA-mimics to enhance miRNA function, or antimiRNAs which inhibit miRNAs, has opened new avenues for the development of therapeutics for dyslipidemias and atherosclerosis, offers a unique approach to treating disease by modulating entire biological pathways. These exciting findings support the development of miRNA antagonists as potential therapeutics for the treatment of dyslipidaemia, atherosclerosis and related metabolic diseases.KEYWORDS: atherosclerosis, lipoprotein, HDL, miRNA

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Structure and Function of Angiopoietin-like Protein 3 (ANGPTL3) in Atherosclerosis

Current Medicinal Chemistry ◽

10.2174/0929867326666190621120523 ◽

2020 ◽

Vol 27 (31) ◽

pp. 5159-5174 ◽

Cited By ~ 4

Author(s):

Xinjie Lu

Keyword(s):

Low Density Lipoprotein ◽

Lipoprotein Metabolism ◽

Density Lipoprotein ◽

Structure And Function ◽

Biological Functions ◽

Pharmacological Management ◽

Vascular Growth ◽

Promising Target ◽

And Function ◽

Systematic Appraisal

Background:Angiopoietin-Like Proteins (ANGPTLs) are structurally related to the angiopoietins. A total of eight ANGPTLs (from ANGPTL1 to ANGPTL8) have been identified so far. Most ANGPTLs possess multibiological functions on lipid metabolism, atherosclerosis, and cancer. Among them, ANGPTL3 has been shown to regulate the levels of Very Low-Density Lipoprotein (VLDL) made by the liver and play a crucial role in human lipoprotein metabolism.Method:A systematic appraisal of ANGPTLs was conducted, focusing on the main features of ANGPTL3 that has a significant role in atherosclerosis.Results:Angiopoietins including ANGPTL3 are vascular growth factors that are highly specific for endothelial cells, perform a variety of other regulatory activities to influence inflammation, and have been shown to possess both pro-atherosclerotic and atheroprotective effects.Conclusion:ANGPTL3 has been demonstrated as a promising target in the pharmacological management of atherosclerosis. However, many questions remain about its biological functions.

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Effect of human scavenger receptor class A overexpression in bone marrow-derived cells on lipoprotein metabolism and atherosclerosis in low density lipoprotein receptor knockout mice

The Journal of Lipid Research ◽

10.1016/s0022-2275(20)33452-0 ◽

2000 ◽

Vol 41 (9) ◽

pp. 1402-1409 ◽

Cited By ~ 5

Author(s):

Nicole Herijgers ◽

Menno P.J. de Winther ◽

Miranda Van Eck ◽

Louis M. Havekes ◽

Marten H. Hofker ◽

...

Keyword(s):

Low Density Lipoprotein ◽

Scavenger Receptor ◽

Lipoprotein Metabolism ◽

Density Lipoprotein ◽

Low Density ◽

Lipoprotein Receptor ◽

Class A ◽

Scavenger Receptor Class ◽

Density Lipoprotein Receptor ◽

Bone Marrow Derived Cells

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Differences in the Effects of Anthocyanin Supplementation on Glucose and Lipid Metabolism According to the Structure of the Main Anthocyanin: A Meta-Analysis of Randomized Controlled Trials

Nutrients ◽

10.3390/nu13062003 ◽

2021 ◽

Vol 13 (6) ◽

pp. 2003

Author(s):

Risa Araki ◽

Akira Yada ◽

Hirotsugu Ueda ◽

Kenichi Tominaga ◽

Hiroko Isoda

Keyword(s):

Lipid Metabolism ◽

Meta Analysis ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Resistance Index ◽

Lipoprotein Cholesterol ◽

Controlled Trials ◽

Oh Groups ◽

Chemical Structures ◽

Glucose And Lipid Metabolism

The effectiveness of anthocyanins may differ according to their chemical structures; however, randomized clinical controlled trials (RCTs) or meta-analyses that examine the consequences of these structural differences have not been reported yet. In this meta-analysis, anthocyanins in test foods of 18 selected RCTs were categorized into three types: cyanidin-, delphinidin-, and malvidin-based. Delphinidin-based anthocyanins demonstrated significant effects on triglycerides (mean difference (MD): −0.24, p < 0.01), low-density lipoprotein cholesterol (LDL-C) (MD: −0.28, p < 0.001), and high-density lipoprotein cholesterol (HDL-C) (MD: 0.11, p < 0.01), whereas no significant effects were observed for cyanidin- and malvidin-based anthocyanins. Although non-significant, favorable effects on total cholesterol (TC) and HDL-C were observed for cyanidin- and malvidin-based anthocyanins, respectively (both p < 0.1). The ascending order of effectiveness on TC and LDL-C was delphinidin-, cyanidin-, and malvidin-based anthocyanins, and the differences among the three groups were significant (both p < 0.05). We could not confirm the significant effects of each main anthocyanin on glucose metabolism; however, insulin resistance index changed positively and negatively with cyanidin- and delphinidin-based anthocyanins, respectively. Therefore, foods containing mainly unmethylated anthocyanins, especially with large numbers of OH groups, may improve glucose and lipid metabolism more effectively than those containing methylated anthocyanins.

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