Regulation of astrocyte lipid metabolism and ApoE secretion by the microglial oxysterol, 25-hydroxycholesterol

Journal of Lipid Research, Journal Year: 2023, Volume and Issue: 64(4), P. 100350 - 100350

Published: Feb. 25, 2023

Neuroinflammation, a major hallmark of Alzheimer's disease and several other neurological psychiatric disorders, is often associated with dysregulated cholesterol metabolism. Relative to homeostatic microglia, activated microglia express higher levels Ch25h, an enzyme that hydroxylates produce 25-hydroxycholesterol (25HC). 25HC oxysterol interesting immune roles stemming from its ability regulate Since astrocytes synthesize in the brain transport it cells via ApoE-containing lipoproteins, we hypothesized secreted may influence lipid metabolism as well extracellular ApoE derived astrocytes. Here, show take up externally added respond altered Extracellular lipoprotein particles increased after treatment without increase Apoe mRNA expression. In mouse astrocytes-expressing human ApoE3 or ApoE4, promoted better than ApoE4. Increased was due elevated efflux Abca1 expression LXRs decreased reuptake suppressed Ldlr inhibition SREBP. also Srebf2, but not Srebf1, leading reduced synthesis affecting fatty acid levels. We further activity sterol-o-acyl transferase led doubling amount cholesteryl esters their concomitant storage droplets. Our results demonstrate important role for regulating astrocyte

Language: Английский

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Ferulic acid combined with different dietary fibers improve glucose metabolism and intestinal barrier function by regulating gut microbiota in high-fat diet-fed mice

Journal of Functional Foods, Journal Year: 2023, Volume and Issue: 112, P. 105919 - 105919

Published: Nov. 28, 2023

Consuming whole grains contributes to the preservation of glucose homeostasis and supports intestinal health, primarily attributed presence functional components like polyphenols dietary fiber. However, it is not well understood how combined influence cereal fiber could benefit metabolism alter gut microbiota. Our results showed that compared ferulic acid alone, with arabinoxylan or β-glucan significantly improve tolerance maintain in high-fat diet-fed mice. Ferulic increased serum GLP-1 level tight junction proteins expression colon. abundance Bifidobacterium Faecalibaculum. Akkermansia norank_f_Muribaculaceae, which were negatively correlated impaired tolerance. Therefore, ameliorates protects barrier integrity by regulating

Language: Английский

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Cholesterol 25-hydroxylase mediates neuroinflammation and neurodegeneration in a mouse model of tauopathy

The Journal of Experimental Medicine, Journal Year: 2024, Volume and Issue: 221(4)

Published: March 1, 2024

Alzheimer’s disease (AD) is characterized by amyloid plaques and neurofibrillary tangles, in addition to neuroinflammation changes brain lipid metabolism. 25-Hydroxycholesterol (25-HC), a known modulator of both inflammation metabolism, produced cholesterol 25-hydroxylase encoded Ch25h expressed as “disease-associated microglia” signature gene. However, whether influences tau-mediated neurodegeneration unknown. Here, we show that the absence resultant reduction 25-HC, there strikingly reduced age-dependent hippocampus entorhinal/piriform cortex PS19 mice, which express P301S mutant human tau transgene. Transcriptomic analyses bulk hippocampal tissue single nuclei revealed deficiency mice strongly suppressed proinflammatory signaling microglia. Our results suggest key role for Ch25h/25-HC potentiating promote neurodegeneration. may represent novel therapeutic target primary tauopathies, AD, other neuroinflammatory diseases.

Language: Английский

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Lipid metabolism as a target for cancer drug resistance: progress and prospects

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: Sept. 28, 2023

Cancer is the world’s leading cause of human death today, and treatment process cancer highly complex. Chemotherapy targeted therapy are commonly used in treatment, emergence drug resistance a significant problem treatment. Therefore, mechanism during has become hot issue current research. A series studies have found that lipid metabolism closely related to resistance. This paper details changes how affects More importantly, most reported combination may lead lipid-related metabolic pathways, which reverse development enhance or rescue sensitivity therapeutic drugs. summarizes progress design targeting improving resistance, providing new ideas strategies for future tumor this reviews issues combining medications with

Language: Английский

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Chemical Inhibition of Sterol Biosynthesis

Biomolecules, Journal Year: 2024, Volume and Issue: 14(4), P. 410 - 410

Published: March 28, 2024

Cholesterol is an essential molecule of life, and its synthesis can be inhibited by both genetic nongenetic mechanisms. Hundreds chemicals that we are exposed to in our daily lives alter sterol biosynthesis. These also encompass various classes FDA-approved medications, including (but not limited to) commonly used antipsychotic, antidepressant, antifungal, cardiovascular medications. medications interfere with enzymes the post-lanosterol biosynthetic pathway, giving rise complex biochemical changes throughout body. The consequences these short- long-term homeostatic disruptions mostly unknown. We performed a comprehensive review literature built catalogue chemical agents capable inhibiting This process identified significant gaps existing knowledge, which fall into two main areas: mechanisms biosynthesis altered arise from inhibitions different steps pathway. outcome reinforced inhibition often-overlooked mechanism result adverse there need develop new safety guidelines for use (novel already approved) side effects, especially during pregnancy.

Language: Английский

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Regulation of Cholesterol Metabolism by Phytochemicals Derived from Algae and Edible Mushrooms in Non-Alcoholic Fatty Liver Disease

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(22), P. 13667 - 13667

Published: Nov. 8, 2022

Cholesterol synthesis occurs in almost all cells, but mainly hepatocytes the liver. is garnering increasing attention for its central role various metabolic diseases. In addition, cholesterol one of most essential elements cells as both a structural source and player participating pathways. Accurate regulation necessary proper metabolism fats body. Disturbances homeostasis have been linked to diseases, such hyperlipidemia non-alcoholic fatty liver disease (NAFLD). For many years, use synthetic chemical drugs has effective against health conditions. Furthermore, from ancient modern times, plant-based considered local medicines, playing important roles human health. Phytochemicals are bioactive natural compounds that derived medicinal plants, fruit, vegetables, roots, leaves, flowers used treat variety They include flavonoids, carotenoids, polyphenols, polysaccharides, vitamins, more. Many these proven antioxidant, anti-inflammatory, antiobesity antihypercholesteremic activity. The multifaceted phytochemicals may provide benefits humans with regard treatment control diseases associated this disorder, NAFLD. recent global environmental climate change, COVID-19 pandemic, current war Europe, other conflicts threatened food security nutrition worldwide. This further emphasizes urgent need sustainable sources functional be included industry dietary habits. review summarizes latest findings on selected sources—algae edible mushrooms—that affect improve or prevent

Language: Английский

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Mitochondrial Cholesterol Metabolites in a Bile Acid Synthetic Pathway Drive Nonalcoholic Fatty Liver Disease: A Revised “Two-Hit” Hypothesis

Cells, Journal Year: 2023, Volume and Issue: 12(10), P. 1434 - 1434

Published: May 20, 2023

The rising prevalence of nonalcoholic fatty liver disease (NAFLD)-related cirrhosis highlights the need for a better understanding molecular mechanisms responsible driving transition hepatic steatosis (fatty liver; NAFL) to steatohepatitis (NASH) and fibrosis/cirrhosis. Obesity-related insulin resistance (IR) is well-known hallmark early NAFLD progression, yet mechanism linking aberrant signaling hepatocyte inflammation has remained unclear. Recently, as function more distinctly defining regulation mechanistic pathways, toxicity mediated by free cholesterol its metabolites emerged fundamental subsequent necroinflammation/fibrosis characteristics NASH. More specifically, signaling, found with IR, leads dysregulation in bile acid biosynthetic pathways intracellular accumulation mitochondrial CYP27A1-derived metabolites, (25R)26-hydroxycholesterol 3β-Hydroxy-5-cholesten-(25R)26-oic acid, which appear be toxicity. These findings bring forth “two-hit” interpretation how NAFL progresses NAFLD: abnormal occurs develops “first hit” that sequentially drives toxic CYP27A1-driven “second hit”. In following review, we examine pathway mitochondria-derived drive development Insights into approaches effective NASH intervention are provided.

Language: Английский

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Cholesteryl ester transfer protein knock‐down in conjunction with a cholesterol‐depleting agent decreases tamoxifen resistance in breast cancer cells

IUBMB Life, Journal Year: 2024, Volume and Issue: 76(9), P. 712 - 730

Published: May 11, 2024

Abstract The cholesterogenic phenotype, encompassing de novo biosynthesis and accumulation of cholesterol, aids cancer cell proliferation survival. Previously, the role cholesteryl ester (CE) transfer protein (CETP) has been implicated in breast aggressiveness, but molecular basis this observation is not clearly understood, which study aims to elucidate. CETP knock‐down resulted a >50% decrease both ‘estrogen receptor‐positive’ (ER+; Michigan Cancer Foundation‐7 (MCF7) cells) ‘triple‐negative’ (TNBC; MDA‐MB‐231) lines. Intriguingly, abrogation together with combination treatment tamoxifen (5 μM) acetyl plumbagin (a cholesterol‐depleting agent) twofold threefold increase apoptosis knockdown also showed decreased intracellular CE levels, lipid raft droplets In addition, RT 2 Profiler PCR array (Qiagen, Germany)‐based gene expression analysis revealed an overall downregulation genes associated cholesterol biosynthesis, signalling drug resistance MCF7 cells post‐ knock‐down. On contrary, MDA‐MB‐231 was reduced through increased efflux targetable surface receptors by endocrine therapy. pilot xenograft mice substantiated 's as survival stunted growth TNBC tumour 86%. principal findings potentiate driver aggressiveness thus targeting could limit via reduction cells, thereby reducing aggressiveness.

Language: Английский

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Tspan6 stimulates the chemoattractive potential of breast cancer cells for B cells in an EV- and LXR-dependent manner

Cell Reports, Journal Year: 2023, Volume and Issue: 42(3), P. 112207 - 112207

Published: March 1, 2023

The immune microenvironment in breast cancer (BCa) is controlled by a complex network of communication between various cell types. Here, we find that recruitment B lymphocytes to BCa tissues via mechanisms associated with cell-derived extracellular vesicles (CCD-EVs). Gene expression profiling identifies the Liver X receptor (LXR)-dependent transcriptional as key pathway controls both CCD-EVs-induced migration cells and accumulation tissues. increased oxysterol ligands for LXR (i.e., 25-hydroxycholesterol 27-hydroxycholesterol) CCD-EVs regulated tetraspanin 6 (Tspan6). Tspan6 stimulates chemoattractive potential an EV- LXR-dependent manner. These results demonstrate tetraspanins control intercellular trafficking oxysterols CCD-EVs. Furthermore, tetraspanin-dependent changes composition signaling axis play role specific tumor microenvironment.

Language: Английский

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Insulin dysregulation drives mitochondrial cholesterol metabolite accumulation: initiating hepatic toxicity in nonalcoholic fatty liver disease

Journal of Lipid Research, Journal Year: 2023, Volume and Issue: 64(5), P. 100363 - 100363

Published: March 24, 2023

CYP7B1 catalyzes mitochondria-derived cholesterol metabolites such as (25R)26-hydroxycholesterol (26HC) and 3β-hydroxy-5-cholesten-(25R)26-oic acid (3βHCA) facilitates their conversion to bile acids. Disruption of 26HC/3βHCA metabolism in the absence leads neonatal liver failure. Disrupted with reduced hepatic expression is also found nonalcoholic steatohepatitis (NASH). The current study aimed understand regulatory mechanism mitochondrial contribution onset NASH. We used Cyp7b1

Language: Английский

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