Caspase-1 as a regulatory molecule of lipid metabolism

Accumulating evidence has shown that miR-34a serves as a posttranscriptional regulatory molecule of lipid metabolism in mammals. However, little studies about miR-34a on lipid metabolism in poultry have been reported until now. To gain insight into the biological functions and action mechanisms of miR-34a on hepatic lipid metabolism in poultry, we firstly investigated the expression pattern of miR-34a-5p, a member of miR-34a family, in liver of chicken, and determined its function in hepatocyte lipid metabolism by miR-34a-5p overexpression and inhibition, respectively. We then validated the interaction between miR-34a-5p and its target using dual-luciferase reporter assay, and explored the action mechanism of miR-34a-5p on its target by qPCR and Western blotting. Additionally, we looked into the function of the target gene on hepatocyte lipid metabolism by gain- and loss-of-function experiments. Our results indicated that miR-34a-5p showed a significantly higher expression level in livers in peak-laying hens than that in pre-laying hens. miR-34a-5p could increase the intracellular levels of triglycerides and total cholesterol in hepatocyte. Furthermore, miR-34a-5p functioned by inhibiting the translation of its target gene, long-chain acyl-CoA synthetase 1 (ACSL1), which negatively regulates hepatocyte lipid content. In conclusion, miR-34a-5p could increase intracellular lipid content by reducing the protein level, without influencing mRNA stability of the ACSL1 gene in chickens.

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25-Hydroxycholesterol-3-sulfate regulates macrophage lipid metabolism via the LXR/SREBP-1 signaling pathway

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90555.2008 ◽

2008 ◽

Vol 295 (6) ◽

pp. E1369-E1379 ◽

Cited By ~ 51

Author(s):

Yongjie Ma ◽

Leyuan Xu ◽

Daniel Rodriguez-Agudo ◽

Xiaobo Li ◽

Douglas M. Heuman ◽

...

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

Fatty Acid Synthase ◽

Lipid Synthesis ◽

Mrna Levels ◽

Intracellular Lipids ◽

Protein Levels ◽

Regulatory Molecule ◽

Fas Mrna

The oxysterol receptor LXR is a key transcriptional regulator of lipid metabolism. LXR increases expression of SREBP-1, which in turn regulates at least 32 genes involved in lipid synthesis and transport. We recently identified 25-hydroxycholesterol-3-sulfate (25HC3S) as an important regulatory molecule in the liver. We have now studied the effects of 25HC3S and its precursor, 25-hydroxycholesterol (25HC), on lipid metabolism as mediated by the LXR/SREBP-1 signaling in macrophages. Addition of 25HC3S to human THP-1-derived macrophages markedly decreased nuclear LXR protein levels. 25HC3S administration was followed by dose- and time-dependent decreases in SREBP-1 mature protein and mRNA levels. 25HC3S decreased the expression of SREBP-1-responsive genes, acetyl-CoA carboxylase-1, and fatty acid synthase (FAS) as well as HMGR and LDLR, which are key proteins involved in lipid metabolism. Subsequently, 25HC3S decreased intracellular lipids and increased cell proliferation. In contrast to 25HC3S, 25HC acted as an LXR ligand, increasing ABCA1, ABCG1, SREBP-1, and FAS mRNA levels. In the presence of 25HC3S, 25HC, and LXR agonist T0901317, stimulation of LXR targeting gene expression was repressed. We conclude that 25HC3S acts in macrophages as a cholesterol satiety signal, downregulating cholesterol and fatty acid synthetic pathways via inhibition of LXR/SREBP signaling. A possible role of oxysterol sulfation is proposed.

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Caspase-1 Inhibition Impacts the Formation of Chondrogenic Nodules, and the Expression of Markers Related to Osteogenic Differentiation and Lipid Metabolism

International Journal of Molecular Sciences ◽

10.3390/ijms22179576 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9576

Author(s):

Alice Ramesova ◽

Barbora Vesela ◽

Eva Svandova ◽

Herve Lesot ◽

Eva Matalova

Keyword(s):

Lipid Metabolism ◽

Treatment Strategies ◽

Treated Group ◽

Bone Cell ◽

Bone Maintenance ◽

Caspase 1 ◽

Cd36 Expression ◽

Inverse Effect ◽

Bone Cell Differentiation ◽

Abnormal Pattern

Caspase-1, as the main pro-inflammatory cysteine protease, was investigated mostly with respect to inflammation-related processes. Interestingly, caspase-1 was identified as being involved in lipid metabolism, which is extremely important for the proper differentiation of chondrocytes. Based on a screening investigation, general caspase inhibition impacts the expression of Cd36 in chondrocytes, the fatty acid translocase with a significant impact on lipid metabolism. However, the engagement of individual caspases in the effect has not yet been identified. Therefore, the hypothesis that caspase-1 might be a candidate here appears challenging. The primary aim of this study thus was to find out whether the inhibition of caspase-1 activity would affect Cd36 expression in a chondrogenic micromass model. The expression of Pparg, a regulator Cd36, was examined as well. In the caspase-1 inhibited samples, both molecules were significantly downregulated. Notably, in the treated group, the formation of the chondrogenic nodules was apparently disrupted, and the subcellular deposition of lipids and polysaccharides showed an abnormal pattern. To further investigate this observation, the samples were subjected to an osteogenic PCR array containing selected markers related to cartilage/bone cell differentiation. Among affected molecules, Bmp7 and Gdf10 showed a significantly increased expression, while Itgam, Mmp9, Vdr, and Rankl decreased. Notably, Rankl is a key marker in bone remodeling/homeostasis and thus is a target in several treatment strategies, including a variety of fatty acids, and is balanced by its decoy receptor Opg (osteoprotegerin). To evaluate the effect of Cd36 downregulation on Rankl and Opg, Cd36 silencing was performed using micromass cultures. After Cd36 silencing, the expression of Rankl was downregulated and Opg upregulated, which was an inverse effect to caspase-1 inhibition (and Cd36 upregulation). These results demonstrate new functions of caspase-1 in chondrocyte differentiation and lipid metabolism-related pathways. The effect on the Rankl/Opg ratio, critical for bone maintenance and pathology, including osteoarthritis, is particularly important here as well.

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25-Hydroxycholesterol-3-sulfate attenuates inflammatory response via PPARγ signaling in human THP-1 macrophages

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00337.2011 ◽

2012 ◽

Vol 302 (7) ◽

pp. E788-E799 ◽

Cited By ~ 23

Author(s):

Leyuan Xu ◽

Shanwei Shen ◽

Yongjie Ma ◽

Jin Koung Kim ◽

Daniel Rodriguez-Agudo ◽

...

Keyword(s):

Lipid Metabolism ◽

Inflammatory Response ◽

Reporter Gene ◽

Inflammatory Responses ◽

Peroxisome Proliferator ◽

Gene Expressions ◽

Protein Levels ◽

Regulatory Molecule ◽

Peroxisome Proliferator Activated Receptors ◽

Reporter Gene Assays

The nuclear receptor peroxisome proliferator-activated receptors (PPARs) are important in regulating lipid metabolism and inflammatory responses in macrophages. Activation of PPARγ represses key inflammatory response gene expressions. Recently, we identified a new cholesterol metabolite, 25-hydroxycholesterol-3-sulfate (25HC3S), as a potent regulatory molecule of lipid metabolism. In this paper, we report the effect of 25HC3S and its precursor 25-hydroxycholesterol (25HC) on PPARγ activity and on inflammatory responses. Addition of 25HC3S to human macrophages markedly increased nuclear PPARγ and cytosol IκB and decreased nuclear NF-κB protein levels. PPARγ response element reporter gene assays showed that 25HC3S significantly increased luciferase activities. PPARγ competitor assay showed that the Ki for 25HC3S was ∼1 μM, similar to those of other known natural ligands. NF-κB-dependent promoter reporter gene assays showed that 25HC3S suppressed TNFα-induced luciferase activities only when cotransfected with pcDNAI-PPARγ plasmid. In addition, 25HC3S decreased LPS-induced expression and release of IL-1β. In the PPARγ-specific siRNA transfected macrophages or in the presence of PPARγ-specific antagonist, 25HC3S failed to increase IκB and to suppress TNFα and IL-1β expression. In contrast to 25HC3S, its precursor 25HC, a known liver X receptor ligand, decreased nuclear PPARγ and cytosol IκB and increased nuclear NF-κB protein levels. We conclude that 25HC3S acts in macrophages as a PPARγ ligand and suppresses inflammatory responses via the PPARγ/IκB/NF-κB signaling pathway.

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A Cytochemical Study of Glucose-6-Phosphatase (G-6-PASE) in Cells Participating in Atherogenesis of Rabbit Aorta

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100115924 ◽

1975 ◽

Vol 33 ◽

pp. 460-461

Author(s):

Sidney D. Kobernick ◽

Edna A. Elfont ◽

Neddra L. Brooks

Keyword(s):

Lipid Metabolism ◽

New Zealand ◽

Aortic Wall ◽

Rabbit Aorta ◽

Plaque Formation ◽

Metabolic Changes ◽

Atherosclerotic Plaques ◽

Cytochemical Study ◽

Cellular Alteration ◽

New Zealand White Rabbits

This cytochemical study was designed to investigate early metabolic changes in the aortic wall that might lead to or accompany development of atherosclerotic plaques in rabbits. The hypothesis that the primary cellular alteration leading to plaque formation might be due to changes in either carbohydrate or lipid metabolism led to histochemical studies that showed elevation of G-6-Pase in atherosclerotic plaques of rabbit aorta. This observation initiated the present investigation to determine how early in plaque formation and in which cells this change could be observed.Male New Zealand white rabbits of approximately 2000 kg consumed normal diets or diets containing 0.25 or 1.0 gm of cholesterol per day for 10, 50 and 90 days. Aortas were injected jin situ with glutaraldehyde fixative and dissected out. The plaques were identified, isolated, minced and fixed for not more than 10 minutes. Incubation and postfixation proceeded as described by Leskes and co-workers.

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