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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Activation of NF-κB signaling regulates ovariectomy-induced bone loss and weight gain

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Journal Year: 2024, Volume and Issue: 1870(7), P. 167320 - 167320

Published: June 25, 2024

Language: Английский

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Integrated Analysis of Gut Microbiome and Adipose Transcriptome Reveals Beneficial Effects of Resistant Dextrin from Wheat Starch on Insulin Resistance in Kunming Mice

Biomolecules, Journal Year: 2024, Volume and Issue: 14(2), P. 186 - 186

Published: Feb. 4, 2024

Systemic chronic inflammation is recognized as a significant contributor to the development of obesity-related insulin resistance. Previous studies have revealed physiological benefits resistant dextrin (RD), including obesity reduction, lower fasting glucose levels, and anti-inflammation. The present study investigated effects RD intervention on resistance (IR) in Kunming mice, expounding mechanisms through gut microbiome transcriptome white adipose. In this eight-week study, we changes tissue weight, glucose–lipid metabolism serum lesions epididymal adipose (eWAT) evaluated via Hematoxylin Eosin (H&E) staining. Moreover, analyzed microbiota composition eWAT assess potential protective intervention. Compared with high-fat, high-sugar diet (HFHSD) group, significantly enhanced homeostasis (e.g., AUC-OGTT, HOMA-IR, p < 0.001), reduced lipid TG, LDL-C, 0.001) levels IL-1β, IL-6, 0.001). also led composition, an increase abundance probiotics Parabacteroides, Faecalibaculum, Muribaculum, 0.05) decrease harmful bacteria (Colidextribacter, 0.05). had noticeable effect gene transcription profile eWAT, KEGG enrichment analysis that differential genes were enriched PI3K/AKT, AMPK, glucose-lipid metabolism, regulation lipolysis adipocytes signaling pathways. findings demonstrated not only ameliorated IR, but remodeled modified eWAT.

Language: Английский

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LC-MS/MS profiling of colon oxysterols and cholesterol precursors in mouse model of ulcerative colitis

Journal of Chromatography A, Journal Year: 2024, Volume and Issue: 1722, P. 464865 - 464865

Published: April 4, 2024

Language: Английский

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Liver specific transgenic expression of CYP7B1 attenuates early Western diet-induced MASLD progression

Journal of Lipid Research, Journal Year: 2025, Volume and Issue: unknown, P. 100757 - 100757

Published: Feb. 1, 2025

Effect of liver specific oxysterol 7α-hydroxylase (CYP7B1) overexpression on the Western diet (WD)-induced metabolic dysfunction-associated steatotic disease (MASLD) progression was studied in mice. Among various hepatic genes impacted during MASLD development, CYP7B1 is consistently suppressed multiple mouse models and human cohorts. enzyme suppression leads to accumulations bioactive oxysterols such as (25R)26-Hydroxycholesterol (26HC) 25-hydroxycholesterol (25HC). We challenged transgenic (CYP7B1hep.tg) overexpressing mice with ad libitum WD feeding. Unlike their wild type (WT) counterparts, WD-fed CYP7B1hep.tg developed no significant hepatotoxicity evidenced by histology, lipid quantifications, serum biomarker analyses. Hepatic 26HC 25HC levels were maintained at basal levels. The comparative gene expression/lipidomic analyses between WT revealed that chronically accumulated initiates LXR/PPAR-mediated fatty acid uptake lipogenesis which surpasses metabolism export; compromising functions. In addition, major pathways related oxidative stress, inflammation immune system including retinol metabolism, arachidonic linoleic significantly All unaltered liver. Furthermore, nucleus but not response WD. This data strongly suggested these two are specifically important nuclear transcriptional regulation for described cytotoxic pathways. conclusion, this study represents a "proof-of-concept" maintaining normal mitochondrial cholesterol expression prevents oxysterol-driven toxicity; thus attenuating progression.

Language: Английский

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The impact of environmental enrichment on energy metabolism in ovariectomized mice

PLoS ONE, Journal Year: 2025, Volume and Issue: 20(4), P. e0320180 - e0320180

Published: April 2, 2025

After menopause, a decline in ovarian function leads to various physical and psychological changes, potentially resulting range of pathological conditions, including abnormalities energy metabolism. In recent years, environmental enrichment, which is characterized by positive comfortable eustress, has been shown improve physiological conditions. This study investigated the effects factors on metabolism menopause model using an ovariectomized (OVX) mouse model. Wild-type female mice (8-week-old) were subjected OVX or sham operation maintained under standard condition (SC), enriched environment (EE), isolated (IS) for 4 weeks. led weight gain disruption circadian rhythms, along with changes metabolic parameters influenced differences housing environments; i.e., EE improved parameters, but IS deteriorated them. Physical activity social interaction that determined these differences. Menopause usually significant transitional period woman’s life, during this can contribute diverse symptoms. Consequently, when implementing interventions alleviate menopause-related not only symptoms also context should be carefully considered.

Language: Английский

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Enhanced Cholesterol Efflux and Atherosclerosis Regression via CEH Gene Delivery Using Galactose-Functionalized Dendrimeric Nanoparticles

ACS Pharmacology & Translational Science, Journal Year: 2025, Volume and Issue: unknown

Published: April 9, 2025

Cholesteryl ester hydrolase (CEH) is a critical enzyme in cholesterol hydrolysis, influencing metabolism and efflux. This study demonstrates that CEH overexpression promotes free efflux from macrophages, thereby reducing the lipid burden existing atherosclerotic plaques. To enable targeted delivery, galactose-functionalized polyamidoamine (PAMAM) dendrimeric nanoparticles were utilized as nanocarriers for hepatic delivery of expression vector. The therapeutic potential plasmid-loaded was evaluated Ldlr-/- mice. Results showed significant reduction total lesion area (21%) aortic arch (23%) compared to baseline. Lesion component analysis revealed marked decreases (36%), (35%), esters (44%). Collectively, these results support an effective strategy enhance mitigate accumulation Moreover, PAMAM demonstrate strong gene system intervention atherosclerosis.

Language: Английский

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StarD5 Plays a Critical Role in the Hepatocyte ER Stress Survival Response

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(9), P. 4157 - 4157

Published: April 27, 2025

The unfolded protein response (UPR) is a highly orchestrated survival initiated in cells under endoplasmic reticulum (ER) stress. Steroidogenic acute regulatory-related lipid transfer domain 5 (StarD5) an ER stress-responsive, cholesterol-binding the regulation of IRE1. Based upon vitro findings, StarD5 delivers protective by translocating cholesterol to plasma membrane (PM) and accompanying changes PM fluidity. study aimed determine if StarD5's ability provide hepatocyte responses translatable vivo conditions. stress mouse livers was induced intraperitoneal injection tunicamycin (Tm). Adenovirus used restore expression StarD5-/- mice. Immunoblotting, histological analysis, measurements were performed. Induction led increased steatosis wild-type (WT) mice, while apoptosis more compared WT as evidenced accumulation cleavage PARP, respectively. Selectively restoring ER-stressed mice blunted effects tunicamycin. appears play critical role through its regulate intracellular homeostasis.

Language: Английский

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StarD5 levels of expression correlate with onset and progression of steatosis and liver fibrosis

AJP Gastrointestinal and Liver Physiology, Journal Year: 2024, Volume and Issue: 326(6), P. G747 - G761

Published: April 9, 2024

Insufficient expression of steroidogenic acute regulatory-related lipid transfer protein 5 (StarD5) on liver cholesterol/lipid homeostasis is not clearly defined. The ablation StarD5 was analyzed in mice a normal or Western diet (WD) to determine its importance hepatic accumulation and fibrosis compared with wild-type (WT) mice. Rescue experiments

Language: Английский

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Blockade of STARD3-mediated cholesterol transport alleviates diabetes-induced podocyte injury by reducing mitochondrial cholesterol accumulation

Life Sciences, Journal Year: 2024, Volume and Issue: 349, P. 122722 - 122722

Published: May 15, 2024

Language: Английский

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