Phospholipid transfer protein (PLTP) deficiency attenuates high fat diet induced obesity and insulin resistance

Song, Guohua; Zong, Cai; Shao, Mingzhu; Yu, Yang; Liu, Qian; Wang, Hui; Qiu, Tingting; Jiao, Peng; Guo, Zheng; Lee, Phoebe; Luo, Yi; Qin, Shucun

doi:10.1016/j.bbalip.2019.06.012

Cited by 16 publications

(7 citation statements)

References 46 publications

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“…Lastly, altering SM turnover at the membrane by phospholipid transfer protein (PLTP) inhibition in mice has found to be protective against diet-induced weight gain and IR. Since PLTP mediates lipid transfer-mostly SM and Chol-from cell membranes to plasma and vice versa, its deficiency was proven to decrease the levels of these two lipid types in lipid rafts and enhance GLUT4 expression and insulin receptor activity in adipocytes [108]. Given its potential as a target in metabolic disorders, this mechanism might be interesting to explore in ATMs.…”

Section: Sphingolipids (Sl)mentioning

confidence: 99%

Rewiring of Lipid Metabolism in Adipose Tissue Macrophages in Obesity: Impact on Insulin Resistance and Type 2 Diabetes

Dahik

Frisdal

Goff

2020

IJMS

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Obesity and its two major comorbidities, insulin resistance and type 2 diabetes, represent worldwide health issues whose incidence is predicted to steadily rise in the coming years. Obesity is characterized by an accumulation of fat in metabolic tissues resulting in chronic inflammation. It is now largely accepted that adipose tissue inflammation underlies the etiology of these disorders. Adipose tissue macrophages (ATMs) represent the most enriched immune fraction in hypertrophic, chronically inflamed adipose tissue, and these cells play a key role in diet-induced type 2 diabetes and insulin resistance. ATMs are triggered by the continuous influx of dietary lipids, among other stimuli; however, how these lipids metabolically activate ATM depends on their nature, composition and localization. This review will discuss the fate and molecular programs elicited within obese ATMs by both exogenous and endogenous lipids, as they mediate the inflammatory response and promote or hamper the development of obesity-associated insulin resistance and type 2 diabetes.

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Section: Sphingolipids (Sl)mentioning

confidence: 99%

Rewiring of Lipid Metabolism in Adipose Tissue Macrophages in Obesity: Impact on Insulin Resistance and Type 2 Diabetes

Dahik

Frisdal

Goff

2020

IJMS

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“…In addition, we found cardiac Nmnat overexpression increased the climbing ability of older flies and lifespan, but it could not resist the adverse the effect of climbing ability and lifespan induced by a HFD. It has been reported that a HFD causes obesity in both animals and flies, which increases the incidence of diabetes, fatty liver, stroke, and hypertension [56][57][58] . This may be the reason that cardiac Nmnat overexpression could not prevent HFD-induced locomotor impairment and lifespan reduction.…”

Section: Discussionmentioning

confidence: 99%

CardiacNmnat/NAD⁺/SIR2 pathways activation mediates endurance exercise resistance to heart defects induced by a high-fat diet in agingDrosophila

Zheng

Lü

et al. 2021

Preprint

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Endurance exercise is an important way to resist and treat a high-fat-diet(HFD)-induced heart defects, but the underlying molecular mechanisms are poorly understood. Here, we used Drosophila to identify whether cardiac Nmnat/NAD+/SIR2 pathways activation could mediate endurance exercise resistance to heart defects. The results showed that endurance exercise activated the cardiac Nmnat/NAD+/SIR2/FOXO pathway and Nmnat/NAD+/SIR2/PGC-1α pathway, including up-regulating cardiac Nmnat, SIR2, FOXO, PGC-1α expression, SOD activity, and NAD+ level, and it prevented HFD-induced or cardiac Nmnat knock-down-induced cardiac lipid accumulation, MDA content and fibrillation increase, and fractional shortening decrease. Cardiac Nmnat overexpression activated heart Nmnat/NAD+/SIR2 pathways and resisted HFD-induced cardiac malfunction, but it could not protect against HFD-induced lifespan reduction and locomotor impairment. Exercise improved lifespan and mobility in cardiac Nmnat knock-down flies. Therefore, current results confirmed that cardiac Nmnat/NAD+/SIR2 pathways were important antagonists of HFD-induced heart defects. The cardiac Nmnat/NAD+/SIR2 pathways activation was the important underlying molecular mechanism of endurance exercise and cardiac Nmnat overexpression against heart defects in Drosophila.

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“…Similarly to SCD1 deficient mice, PLTP knock-out animals show reduced high fat diet-induced obesity. In addition, they presented decreased levels of sphingomyelin and free cholesterol (47).…”

Section: Discussionmentioning

confidence: 99%

Transcriptome analysis of the NR1H3 mouse model of multiple sclerosis reveals a pro-inflammatory phenotype with dysregulation of lipid metabolism and immune response genes

Vilariño‐Güell

Encarnacion

et al. 2021

Preprint

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BackgroundThe development of effective treatments for multiple sclerosis (MS), and in particular its progressive forms, is hampered by the lack of etiologically relevant cellular and animal models of human disease. Models that recapitulate the biological and pathological processes leading to the onset and progression of MS in patients are likely to afford better translational efficacy. Following the discovery of the NR1H3 p.Arg415Gln pathogenic mutation for progressive MS in two Canadian families, we developed a knock-in mouse model harboring a homologous mutation in the endogenous gene to provide a more physiologically relevant model of human MS.MethodsGene expression was evaluated in constitutive heterozygote (which recapitulates the human disease genotype) and homozygote Nr1h3 p.Arg413Gln knock-in mice on a C57BL/6 background, and compared to wild-type littermates. AmpliSeq Transcriptome Mouse Gene Expression kits analyzed on an Ion Proton sequencer were used to generate the gene expression profiles of spleen, liver, brain and spinal cord tissue from three-month-old male and female mice. Differential expression between genotypes was assessed with DESeq2, and Gene Ontologies pathways enrichment analysis performed with DAVID v6.8. Benjamini-Hochberg false discovery rate (FDR) correction for multiple testing was applied.ResultsTranscriptome analysis of spleen tissue from Nr1h3 p.Arg413Gln mice revealed 23 significantly dysregulated genes (FDR<0.05) with greater than a two-fold change in expression. These include CD5 antigen-like (Cd5l), complement component 6 (C6), procollagen C-endopeptidase enhancer 2 (Pcolce2), interleukin 22 receptor, alpha 2 (Il22ra2), and T cell immunoglobulin and mucin domain containing 4 (Timd4). Gene Ontology enrichment analysis support upregulation of cell cycle pathways and downregulation of immune system response in splenic cells. The liver transcriptome identified 27 significantly dysregulated genes with greater than a two-fold change in expression compared to wild-type littermates. Cd5l, Timd4, C-C motif chemokine receptor 3 (Ccr3), ADAM metallopeptidase domain 11 (Adam11) and macrophage expressed 1 (Mpeg1) were amongst those most significantly dysregulated. Enrichment analysis supported altered immune function with upregulation of sterol and steroid metabolic processes and downregulation of fatty acid biosynthesis and inflammatory and immune system responses. Although brain and spinal cord transcriptome profiles identified several genes significantly dysregulated in Nr1h3 mice compared to wild-type littermates (FDR<0.05), none presented greater than two-fold changes in gene expression.DiscussionThe analysis of the Nr1h3 p.Arg413Gln mouse model of MS suggests that the predominance of a pro-inflammatory over a healing or reparative phenotype, combined with deficiencies in myelination and remyelination, are the biological mechanisms implicated in the onset of MS and the development of a more severe progressive disease course observed in patients with NR1H3 mutations. Association of NR1H3 common variants with MS risk indicates that the disruption of these biological and immunological processes is not only informative for familial forms of disease but MS patients at large. Differences in transcriptome profiles underline the value of this model for the development and validation of novel therapeutic strategies and ultimately treatments with the potential to delay or even halt the onset of progressive MS and to ameliorate the severity of clinical symptoms.

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Phospholipid transfer protein (PLTP) deficiency attenuates high fat diet induced obesity and insulin resistance

Cited by 16 publications

References 46 publications

Rewiring of Lipid Metabolism in Adipose Tissue Macrophages in Obesity: Impact on Insulin Resistance and Type 2 Diabetes

Rewiring of Lipid Metabolism in Adipose Tissue Macrophages in Obesity: Impact on Insulin Resistance and Type 2 Diabetes

CardiacNmnat/NAD⁺/SIR2 pathways activation mediates endurance exercise resistance to heart defects induced by a high-fat diet in agingDrosophila

Transcriptome analysis of the NR1H3 mouse model of multiple sclerosis reveals a pro-inflammatory phenotype with dysregulation of lipid metabolism and immune response genes

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Phospholipid transfer protein (PLTP) deficiency attenuates high fat diet induced obesity and insulin resistance

Cited by 16 publications

References 46 publications

Rewiring of Lipid Metabolism in Adipose Tissue Macrophages in Obesity: Impact on Insulin Resistance and Type 2 Diabetes

Rewiring of Lipid Metabolism in Adipose Tissue Macrophages in Obesity: Impact on Insulin Resistance and Type 2 Diabetes

CardiacNmnat/NAD+/SIR2 pathways activation mediates endurance exercise resistance to heart defects induced by a high-fat diet in agingDrosophila

Transcriptome analysis of the NR1H3 mouse model of multiple sclerosis reveals a pro-inflammatory phenotype with dysregulation of lipid metabolism and immune response genes

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CardiacNmnat/NAD⁺/SIR2 pathways activation mediates endurance exercise resistance to heart defects induced by a high-fat diet in agingDrosophila