ResearchPad - 303 https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Novel defatting strategies reduce lipid accumulation in primary human culture models of liver steatosis]]> https://www.researchpad.co/article/Na3436f88-3c1d-4e74-8663-e5074ac00bc5 Summary: This study describes a defatting cocktail that has been proven to function in three relevant steatotic human culture models without cytotoxicity, and which could be employed in the reduction of steatosis in donor livers during liver transplantation.

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<![CDATA[Integrated lipidomic and transcriptomic analyses identify altered nerve triglycerides in mouse models of prediabetes and type 2 diabetes]]> https://www.researchpad.co/article/N4b90af06-65b4-42ae-805c-cf43b9de0c5f

ABSTRACT

Peripheral neuropathy (PN) is a complication of prediabetes and type 2 diabetes (T2D). Increasing evidence suggests that factors besides hyperglycaemia contribute to PN development, including dyslipidaemia. The objective of this study was to determine differential lipid classes and altered gene expression profiles in prediabetes and T2D mouse models in order to identify the dysregulated pathways in PN. Here, we used high-fat diet (HFD)-induced prediabetes and HFD/streptozotocin (STZ)-induced T2D mouse models that develop PN. These models were compared to HFD and HFD-STZ mice that were subjected to dietary reversal. Both untargeted and targeted lipidomic profiling, and gene expression profiling were performed on sciatic nerves. Lipidomic and transcriptomic profiles were then integrated using complex correlation analyses, and biological meaning was inferred from known lipid-gene interactions in the literature. We found an increase in triglycerides (TGs) containing saturated fatty acids. In parallel, transcriptomic analysis confirmed the dysregulation of lipid pathways. Integration of lipidomic and transcriptomic analyses identified an increase in diacylglycerol acyltransferase 2 (DGAT2), the enzyme required for the last and committed step in TG synthesis. Increased DGAT2 expression was present not only in the murine models but also in sural nerve biopsies from hyperlipidaemic diabetic patients with PN. Collectively, these findings support the hypothesis that abnormal nerve-lipid signalling is an important factor in peripheral nerve dysfunction in both prediabetes and T2D.

This article has an associated First Person interview with the joint first authors of the paper.

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<![CDATA[Cell-specific and athero-protective roles for RIPK3 in a murine model of atherosclerosis]]> https://www.researchpad.co/article/N6f634e67-b548-4d3a-a716-0f4ee60039b6

ABSTRACT

Receptor-interacting protein kinase 3 (RIPK3) was recently implicated in promoting atherosclerosis progression through a proposed role in macrophage necroptosis. However, RIPK3 has been connected to numerous other cellular pathways, which raises questions about its actual role in atherosclerosis. Furthermore, RIPK3 is expressed in a multitude of cell types, suggesting that it may be physiologically relevant to more than just macrophages in atherosclerosis. In this study, Ripk3 was deleted in macrophages, endothelial cells, vascular smooth muscle cells or globally on the Apoe−/− background using Cre-lox technology. To induce atherosclerosis progression, male and female mice were fed a Western diet for three months before tissue collection and analysis. Surprisingly, necroptosis markers were nearly undetectable in atherosclerotic aortas. Furthermore, en face lesion area was increased in macrophage- and endothelial-specific deletions of Ripk3 in the descending and abdominal regions of the aorta. Analysis of bone-marrow-derived macrophages and cultured endothelial cells revealed that Ripk3 deletion promotes expression of monocyte chemoattractant protein 1 (MCP-1) and E-selectin in these cell types, respectively. Western blot analysis showed upregulation of MCP-1 in aortas with Ripk3-deficient macrophages. Altogether, these data suggest that RIPK3 in macrophages and endothelial cells protects against atherosclerosis through a mechanism that likely does not involve necroptosis. This protection may be due to RIPK3-mediated suppression of pro-inflammatory MCP-1 expression in macrophages and E-selectin expression in endothelial cells. These findings suggest a novel and unexpected cell-type specific and athero-protective function for RIPK3.

This article has an associated First Person interview with the first author of the paper.

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<![CDATA[Ablation of Bscl2/seipin in hepatocytes does not cause metabolic dysfunction in congenital generalised lipodystrophy]]> https://www.researchpad.co/article/Nea4a1ac6-937b-4bdc-bfd2-28951619e410

ABSTRACT

Mutations affecting the BSCL2 gene cause the most severe form of congenital generalised lipodystrophy (CGL). Affected individuals develop severe metabolic complications including diabetes and hepatic steatosis. Bscl2-deficient mice almost entirely reproduce the CGL phenotype. Adipose tissue-specific loss of Bscl2 is also sufficient to cause early-onset generalised lipodystrophy in mice. However, these mice do not show severe metabolic dysfunction, even when challenged with a high-fat diet. Germline Bscl2 loss in mice and BSCL2 disruption in humans causes severe hepatic steatosis, and the encoded protein, seipin, has acknowledged roles in lipid accumulation. Given the critical role of the liver in glucose regulation, we speculated that intact hepatic Bscl2 expression may protect adipose tissue-specific Bscl2-deficient mice from metabolic disease. To investigate this, we generated a novel mouse model in which Bscl2 has been deleted in both adipose tissue and hepatocytes simultaneously using an adeno-associated viral vector. Despite achieving efficient disruption of Bscl2 in the liver, hepatic lipid accumulation and metabolic homeostasis was unaffected in mice fed a high-fat diet for 4 weeks. We also investigated the consequences of BSCL2 ablation in the human hepatocyte HepG2 cell line using CRISPR/Cas9 genome editing. No significant increases in lipid accumulation were observed in BSCL2 knockout cell lines. Overall, we reveal that Bscl2/BSCL2 does not appear to play a cell-autonomous role in the regulation of lipid accumulation in the liver. Loss of hepatic BSCL2 is therefore unlikely to contribute significantly to the development of hepatic steatosis or metabolic dysfunction in this form of CGL.

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