Accumulation of cholesterol suppresses oxidative phosphorylation and altered responses to inflammatory stimuli of macrophages

Chiu, Yi‐Chun; Chu, Pei-Wen; Lin, Hua‐Ching; Chen, Shau-Kwaun

doi:10.1016/j.bbrep.2021.101166

Cited by 6 publications

(4 citation statements)

References 31 publications

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“…And yet, subsequent analyses of associated biomarkers revealed no such differences between control and test females. Indeed, we observed similar circulating concentrations of sLRP-1, various pro-inflammatory cytokines including TNF-α, and free cholesterol, which suggested that disruption of circulating ligand trafficking 64 , peripheral inflammation 65 , and cholesterol homeostasis 66 , respectively, did not occur at endpoint despite the marked effects on hepatic LRP-1 concentrations. Perhaps, these findings are explained by the well-established acute nature of APAP-induced hepatotoxicity and elevated tolerance of female mice.…”

Section: Discussionmentioning

confidence: 52%

Elderly mice with history of acetaminophen intoxication display worsened cognitive impairment and persistent elevation of astrocyte and microglia burden

Catumbela,

Morales

2024

Sci Rep

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Acetaminophen (APAP) is a leading cause of acute liver failure. The effect of APAP metabolite’s effects in the periphery are well characterized; however, associated consequences in the brain remain poorly understood. Animal studies on this subject are few and reveal that frequent APAP intake can trigger cerebral abnormalities that vary depending on the subject’s age. Alarmingly, experimental efforts have yet to examine associated consequences in elderly hosts, who correspond to the highest risk of medication overload, impaired drug clearance, and cognitive deficits. Here, we interrogated the cerebral and peripheral pathology of elderly mice submitted to monthly episodes of APAP intoxication since a young adult age. We found that weeks after the final episode of recurrent APAP exposure, mice exhibited worsened non-spatial memory deficit whereas spatial memory performance was unaltered. Interestingly, one month after the period of APAP intoxication, these mice showed increased glial burden without associated drivers, namely, blood–brain barrier disruption, cholesterol accumulation, and elevation of inflammatory molecules in the brain and/or periphery. Our experimental study reveals how recurrent APAP exposure affects the cognitive performance and cellular events in elderly brains. These data suggest that APAP-containing pharmacological interventions may foreshadow the elevated risk of neuropsychiatric disorders that afflict elderly populations.

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Section: Discussionmentioning

confidence: 52%

Elderly mice with history of acetaminophen intoxication display worsened cognitive impairment and persistent elevation of astrocyte and microglia burden

Catumbela,

Morales

2024

Sci Rep

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“…In mouse Mø treated with soluble (free) cholesterol, it was observed that cholesterol was absorbed and accumulated in the cytoplasm and mitochondria, leading to increased mitochondrial mass, decreased oxygen consumption rate, and OXPHOS (103). This suggests that an accumulation of cholesterol in cellular compartments, such as the mitochondria, could cause changes in mitochondrial metabolism and bioenergetics.…”

Section: Impaired Mitochondrial Metabolism In Ibdmentioning

confidence: 99%

The role of cholesterol and mitochondrial bioenergetics in activation of the inflammasome in IBD

et al. 2022

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Inflammatory Bowel Disease (IBD) is characterized by a loss of intestinal barrier function caused by an aberrant interaction between the immune response and the gut microbiota. In IBD, imbalance in cholesterol homeostasis and mitochondrial bioenergetics have been identified as essential events for activating the inflammasome-mediated response. Mitochondrial alterations, such as reduced respiratory complex activities and reduced production of tricarboxylic acid (TCA) cycle intermediates (e.g., citric acid, fumarate, isocitric acid, malate, pyruvate, and succinate) have been described in in vitro and clinical studies. Under inflammatory conditions, mitochondrial architecture in intestinal epithelial cells is dysmorphic, with cristae destruction and high dynamin-related protein 1 (DRP1)-dependent fission. Likewise, these alterations in mitochondrial morphology and bioenergetics promote metabolic shifts towards glycolysis and down-regulation of antioxidant Nuclear erythroid 2-related factor 2 (Nrf2)/Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) signaling. Although the mechanisms underlying the mitochondrial dysfunction during mucosal inflammation are not fully understood at present, metabolic intermediates and cholesterol may act as signals activating the NLRP3 inflammasome in IBD. Notably, dietary phytochemicals exhibit protective effects against cholesterol imbalance and mitochondrial function alterations to maintain gastrointestinal mucosal renewal in vitro and in vivo conditions. Here, we discuss the role of cholesterol and mitochondrial metabolism in IBD, highlighting the therapeutic potential of dietary phytochemicals, restoring intestinal metabolism and function.

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“…2 b-c). Additionally, FC accumulation also can impair mitochondrial respiration and disrupt the assembly of mitochondrial respiratory complex [ 21 , 22 ]. Thus, the mitochondrial oxygen consumption rate (OCR) was evaluated by Seahorse XFe96 analyzer.…”

Section: Resultsmentioning

confidence: 99%

MicroRNA-379-5p regulates free cholesterol accumulation and relieves diet induced-liver damage in db/db mice via STAT1/HMGCS1 axis

Dong

et al. 2022

Mol Biomed

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Lipotoxicity induced by the overload of lipid in the liver, especially excess free cholesterol (FC), has been recognized as one of driving factors in the transition from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH). MicroRNA (miR)-379-5p has been reported to play regulatory roles in hepatic triglyceride homeostasis, but the relationship of miR-379-5p and hepatic cholesterol homeostasis has never been touched. In the current study, we found that hepatic miR-379-5p levels were decreased obviously in NAFLD patients and model mice compared with their controls. Moreover, miR-379-5p was discovered to be able to inhibit intracellular FC accumulation and alleviate mitochondrial damage induced by palmitic acid (PA) in vitro. Furthermore, overexpression of miR-379-5p in HFHC-fed db/db mice could reduce the level of hepatic total cholesterol (TC) and FC, and ameliorate hepatic injury reflected by the lower serum alanine aminotransferase (ALT) and aspartate transaminase (AST). Subsequently, by combining spectrometry (MS) and luciferase assay, we identified miR-379-5p suppressed STAT1 through transcriptional and translational regulation. Finally, we confirmed that STAT1 was a transcriptional factor of HMGCS1. In conclusion, miR-379-5p inhibits STAT1 expression and regulates cholesterol metabolism through the STAT1/HMGCS1 axis, suggesting miR-379-5p might be applied to improve lipotoxicity in the future.

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Accumulation of cholesterol suppresses oxidative phosphorylation and altered responses to inflammatory stimuli of macrophages

Cited by 6 publications

References 31 publications

Elderly mice with history of acetaminophen intoxication display worsened cognitive impairment and persistent elevation of astrocyte and microglia burden

Elderly mice with history of acetaminophen intoxication display worsened cognitive impairment and persistent elevation of astrocyte and microglia burden

The role of cholesterol and mitochondrial bioenergetics in activation of the inflammasome in IBD

MicroRNA-379-5p regulates free cholesterol accumulation and relieves diet induced-liver damage in db/db mice via STAT1/HMGCS1 axis

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