Cocaine and HIV-1 Tat disrupt cholesterol homeostasis in astrocytes: Implications for HIV-associated neurocognitive disorders in cocaine user patients. | LitMetric
Cholesterol synthesis and clearance by astrocytes are tightly regulated to maintain constant levels within the brain. In this context, liver X receptors (LXRs) are the master regulators of cholesterol homeostasis in the central nervous system (CNS). Increasing levels of cholesterol in astrocytes trigger LXR activation leading to the transcription of target genes involved in cholesterol trafficking and efflux, including apolipoprotein E, cytochrome P450 enzymes, sterol regulatory binding protein, and several ATP-binding cassette transporter proteins. The disturbance of LXR signaling in the brain can lead to significant dysfunctions in cholesterol homeostasis, and disruptions in this pathway have been implicated in numerous neurological diseases including Alzheimer's disease and Huntington's disease. HIV infection of the CNS in combination with cocaine use is associated with astrocyte and neuronal energy deficit and damage. We propose that dysregulation in CNS cholesterol metabolism may be involved in the progression of HIV-associated neurocognitive disorders (HAND) and in cocaine-mediated neurocognitive impairments. We hypothesize that exposure of astrocytes to cocaine and the HIV protein Tat will disrupt LXR signaling. Alterations in these pathways will in turn, affect cholesterol bioavailability for neurons. Our data show that exposure of astrocytes to cocaine and HIV-Tat significantly decreases LXRβ levels, downstream signaling and bioavailability of cholesterol. Taken together, these data uncover novel alterations in a bioenergetic pathway in astrocytes exposed to cocaine and the HIV protein Tat. Results from these studies point to a new pathway in the CNS that may contribute to HAND in HIV+ cocaine user individuals.
Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of chronic liver conditions, ranging from simple steatosis to nonalcoholic steatohepatitis, which may progress to fibrosis/cirrhosis. Here, the GSE163211 data set was analyzed, and Asah1 (encoding acid ceramidase) was identified as a crucial lysosomal gene that positively correlated with NAFLD stages in obese patients. To evaluate the role of Asah1 in the progression of NAFLD, Asah1/Alb mice (hepatocyte-specific deletion of Asah1) and Asah1 floxed (Asah1/wild-type) mice were fed with either a normal diet or a high-fat, high-cholesterol paigen diet (PD) for 20 weeks.
The regulation of oxygen homeostasis is critical in physiology and disease pathogenesis. High Altitude environment or hypoxia (lack of oxygen) can lead to adverse health conditions such as HAPE despite initial adaptive physiological responses. Studying genetic, hematological and biochemical, and the physiological outcomes of hypoxia together could yield a comprehensive understanding and potentially uncover valuable biomarkers for predicting responses.
Manganese (Mn), a trace element, has been documented to exert an important role in the metabolism of cholesterol. Cholesterol gallstone (CG) pathogenesis is directly linked to biliary cholesterol imbalance which could be due to diabetes complications or mismanagement. NF-κβ pathway, an inflammatory regulator, has been implicated in metabolic disease especially in the context of diabetes and gallstone formation.
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Membranes are molecular interfaces that compartmentalize cells to control the flow of nutrients and information. These functions are facilitated by diverse collections of lipids, nearly all of which are distributed asymmetrically between the two bilayer leaflets. Most models of biomembrane structure and function often include the implicit assumption that these leaflets have similar abundances of phospholipids.
