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Genes & DevelopmentGATA4 is a transcription factor known for its crucial role in the development of many tissues, including the liver; however, its role in adult liver metabolism is...
GATA4 is a transcription factor known for its crucial role in the development of many tissues, including the liver; however, its role in adult liver metabolism is unknown. Here, using high-throughput sequencing technologies, we identified GATA4 as a transcriptional regulator of metabolism in the liver. GATA4 expression is elevated in response to refeeding, and its occupancy is increased at enhancers of genes linked to fatty acid and lipoprotein metabolism. Knocking out GATA4 in the adult liver (Gata4LKO) decreased transcriptional activity at GATA4 binding sites, especially during feeding. Gata4LKO mice have reduced plasma HDL cholesterol and increased liver triglyceride levels. The expression of a panel of GATA4 binding genes involved in hepatic cholesterol export and triglyceride hydrolysis was down-regulated in Gata4LKO mice. We further demonstrate that GATA4 collaborates with LXR nuclear receptors in the liver. GATA4 and LXRs share a number of binding sites, and GATA4 was required for the full transcriptional response to LXR activation. Collectively, these results show that hepatic GATA4 contributes to the transcriptional control of hepatic and systemic lipid homeostasis.
Topics: Mice; Animals; Orphan Nuclear Receptors; Liver X Receptors; Liver; Homeostasis; Cholesterol; Triglycerides; Lipid Metabolism; Mice, Inbred C57BL; GATA4 Transcription Factor
PubMed: 36522129
DOI: 10.1101/gad.350145.122 -
Cellular and Molecular Life Sciences :... Mar 2012Cholesterol homeostasis is among the most intensely regulated processes in biology. Since its isolation from gallstones at the time of the French Revolution, cholesterol... (Review)
Review
Cholesterol homeostasis is among the most intensely regulated processes in biology. Since its isolation from gallstones at the time of the French Revolution, cholesterol has been extensively studied. Insufficient or excessive cellular cholesterol results in pathological processes including atherosclerosis and metabolic syndrome. Mammalian cells obtain cholesterol from the circulation in the form of plasma lipoproteins or intracellularly, through the synthesis of cholesterol from acetyl coenzyme A (acetyl-CoA). This process is tightly regulated at multiple levels. In this review, we provide an overview of the multiple mechanisms by which cellular cholesterol metabolism is regulated. We also discuss the recent advances in the post-transcriptional regulation of cholesterol homeostasis, including the role of small non-coding RNAs (microRNAs). These novel findings may open new avenues for the treatment of dyslipidemias and cardiovascular diseases.
Topics: Animals; Biological Transport; Cardiovascular Diseases; Cholesterol; Homeostasis; Humans; Hydroxymethylglutaryl CoA Reductases; MicroRNAs
PubMed: 22009455
DOI: 10.1007/s00018-011-0857-5 -
Nutrients Aug 2022Lipid rafts in cell plasma membranes play a critical role in the life cycle of many viruses. However, the involvement of membrane cholesterol-rich lipid rafts in the...
Lipid rafts in cell plasma membranes play a critical role in the life cycle of many viruses. However, the involvement of membrane cholesterol-rich lipid rafts in the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into target cells is not well known. In this study, we investigated whether the presence of cholesterol-rich microdomains is required for the entry of SARS-CoV-2 into host cells. Our results show that depletion of cholesterol in the rafts by methyl-beta-cyclodextrin (MβCD) treatment impaired the expression of the cell surface receptor angiotensin-converting enzyme 2 (ACE2), resulting in a significant increase in SARS-CoV-2 entry into cells. The effects exerted by MβCD could be substantially reversed by exogenous cholesterol replenishment. In contrast, disturbance of intracellular cholesterol homeostasis by statins or siRNA knockdown of key genes involved in the cholesterol biosynthesis and transport pathways reduced SARS-CoV-2 entry into cells. Our study also reveals that SREBP2-mediated cholesterol biosynthesis is involved in the process of SARS-CoV-2 entry in target cells. These results suggest that the host membrane cholesterol-enriched lipid rafts and cellular cholesterol homeostasis are essential for SARS-CoV-2 entry into cells. Pharmacological manipulation of intracellular cholesterol might provide new therapeutic strategies to alleviate SARS-CoV-2 entry into cells.
Topics: COVID-19; Cholesterol; Homeostasis; Humans; Membrane Microdomains; SARS-CoV-2; Virus Internalization
PubMed: 36014919
DOI: 10.3390/nu14163417 -
International Journal of Molecular... Nov 2020Cholesterol is an essential cell component that functions to create and maintain all kinds of cell membranes and lipoprotein particles. It is crucial to maintain the... (Review)
Review
Cholesterol is an essential cell component that functions to create and maintain all kinds of cell membranes and lipoprotein particles. It is crucial to maintain the proper amount of cholesterol at both the cellular and systemic level. Recently, the importance of cholesterol has been reported not only in various cell development processes but also in the development of diseases. Furthermore, the involvement of long non-coding RNAs (lncRNAs), which are regarded as important epigenetic regulators in gene expression, has also been reported in cholesterol homeostasis. It is thus necessary to summarize the research on lncRNAs related to cholesterol with increased interest. This review organized the role of lncRNAs according to the major issues in cholesterol homeostasis: efflux, metabolism and synthesis, and disease process.
Topics: Cholesterol; Homeostasis; Humans; Lipid Metabolism; Metabolic Diseases; RNA, Long Noncoding
PubMed: 33172104
DOI: 10.3390/ijms21218337 -
Biochimica Et Biophysica Acta.... Sep 2020Starting with cholesterol homeostasis, the first part of the review addresses various aspects of cholesterol metabolism in neuronal and glial cells and the mutual... (Review)
Review
Starting with cholesterol homeostasis, the first part of the review addresses various aspects of cholesterol metabolism in neuronal and glial cells and the mutual crosstalk between the two cell types, particularly the transport of cholesterol from its site of synthesis to its target loci in neuronal cells, discussing the multiple mechanistic aspects and transporter systems involved. Statins are next analyzed from the point of view of their chemical structure and its impingement on their pharmacological properties and permeability through cell membranes and the blood-brain barrier in particular. The following section then discusses the transcriptional effects of statins and the changes they induce in brain cell genes associated with a variety of processes, including cell growth, signaling and trafficking, uptake and synthesis of cholesterol. We review the effects of statins at the cellular level, analyzing their impact on the cholesterol composition of the nerve and glial cell plasmalemma, neurotransmitter receptor mobilization, myelination, dendritic arborization of neurons, synaptic vesicle release, and cell viability. Finally, the role of statins in disease is exemplified by Alzheimer and Parkinson diseases and some forms of epilepsy, both in animal models and in the human form of these pathologies.
Topics: Alzheimer Disease; Brain; Cell Membrane Permeability; Cholesterol; Homeostasis; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Neuroglia; Neurons; Parkinson Disease; Synaptic Vesicles
PubMed: 32387399
DOI: 10.1016/j.bbamem.2020.183340 -
Arteriosclerosis, Thrombosis, and... May 2023Atherosclerosis is complex chronic disease characterized by intimal cholesterol accumulation and vascular inflammation. There is a well-established relationship of... (Review)
Review
Atherosclerosis is complex chronic disease characterized by intimal cholesterol accumulation and vascular inflammation. There is a well-established relationship of hypercholesterolemia and inflammation with atherosclerosis. However, the link between inflammation and cholesterol is not completely understood. Myeloid cells, in particular, monocytes, macrophages, and neutrophils play essential roles in the pathogenesis of atherosclerotic cardiovascular disease. It is well known that macrophages accumulate cholesterol, forming foam cells, which drive atherosclerosis-associated inflammation. However, the interaction between cholesterol and neutrophils remains poorly defined-an important gap in the literature given that neutrophils represent up to 70% of total circulating leukocytes in humans. Elevated levels of biomarkers of neutrophil activation (myeloperoxidase and neutrophil extracellular traps) and higher absolute neutrophil counts are both associated with increased rates of cardiovascular events. Neutrophils contain the necessary machinery to uptake, synthesize, efflux and esterify cholesterol; yet, the functional consequence of dysregulated cholesterol homeostasis on neutrophil activity remains poorly defined. Preclinical animal data suggest a direct link between cholesterol metabolism and hematopoiesis, although current evidence in humans has been unable to corroborate such findings. This review will explore the impact of impaired cholesterol homeostasis neutrophils and draw focus on the discordant data from animal models and atherosclerotic disease in humans.
Topics: Animals; Humans; Neutrophils; Atherosclerosis; Cholesterol; Inflammation; Homeostasis
PubMed: 36951066
DOI: 10.1161/ATVBAHA.123.316246 -
Journal of Zhejiang University.... May 2019Bile acids (BAs) are originally known as detergents essential for the digestion and absorption of lipids. In recent years, extensive research has unveiled new functions... (Review)
Review
Bile acids (BAs) are originally known as detergents essential for the digestion and absorption of lipids. In recent years, extensive research has unveiled new functions of BAs as gut hormones that modulate physiological and pathological processes, including glucose and lipid metabolism, energy expenditure, inflammation, tumorigenesis, cardiovascular disease, and even the central nervous system in addition to cholesterol homeostasis, enterohepatic protection and liver regeneration. BAs are closely linked with gut microbiota which might explain some of their crucial roles in organs. The signaling actions of BAs can also be mediated through specific nuclear receptors and membrane-bound G protein-coupled receptors. Several pharmacological agents or bariatric surgeries have demonstrated efficacious therapeutic effects on metabolic diseases through targeting BA signaling. In this mini-review, we summarize recent advances in bile-ology, focusing on its translational studies.
Topics: Animals; Bile Acids and Salts; Carcinogenesis; Cholesterol; Detergents; Diabetes Mellitus, Type 2; Drug Discovery; Gastrointestinal Microbiome; Homeostasis; Humans; Inflammation; Inflammatory Bowel Diseases; Lipid Metabolism; Lipids; Metabolic Diseases; Mice; Non-alcoholic Fatty Liver Disease; Obesity; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Translational Research, Biomedical
PubMed: 31090267
DOI: 10.1631/jzus.B1900158 -
Current Issues in Molecular Biology 2017Liver X receptors α (LXRα) and β (LXRβ) are essential for protection against cardiovascular diseases. LXRs are members of the nuclear receptor superfamily of... (Review)
Review
Liver X receptors α (LXRα) and β (LXRβ) are essential for protection against cardiovascular diseases. LXRs are members of the nuclear receptor superfamily of DNA-binding transcription factors and act as sensors of cholesterol homeostasis. In this review, we introduce LXRs and briefly describe the roles of LXRs in reverse cholesterol transport and trans-intestinal cholesterol efflux. We discuss LXR agonists and the downstream genes of LXRs that are involved in the regulation of cholesterol transport. In addition, we describe the cardioprotective effects of LXRs against atherosclerosis, myocardial ischemia/reperfusion injury, diabetic cardiomyopathy, and myocardial hypertrophy. Finally, we expand our discussion to the actions of LXRs in atherosclerosis and suggest several potential research avenues that may be of interest to clinicians and basic scientists. The information included herein may be useful for the design of future experimental research studies and may advance the investigation of LXRs as therapeutic targets.
Topics: Animals; Cardiovascular Diseases; Cholesterol; Homeostasis; Humans; Lipid Metabolism; Liver X Receptors
PubMed: 27669666
DOI: 10.21775/cimb.022.041 -
The Journal of Nutrition Aug 2020
Topics: Cholesterol; Daucus carota; Homeostasis; Humans; Lipid Metabolism; Retinoids; beta Carotene
PubMed: 32747944
DOI: 10.1093/jn/nxaa189 -
Nutrients Mar 2021Current strategies targeting serum cholesterol bring limited benefits to mortality and macrovascular events prevention among hemodialysis patients. Direct measurements...
Current strategies targeting serum cholesterol bring limited benefits to mortality and macrovascular events prevention among hemodialysis patients. Direct measurements and analysis on circulating markers of cholesterol homeostasis could be promising solutions to this bottleneck. We prospectively enrolled 90 maintenance hemodialysis patients and 9 healthy controls in 2019 for 1 year. We measured circulating desmosterol and lathosterol as markers for cholesterol synthesis and campesterol and sitosterol for cholesterol absorption. At baseline, hemodialysis patients showed higher levels of campesterol ( = 0.023) compared to healthy controls. During follow-up, we identified 14 (15.4%) patients who experienced macrovascular events. Comparisons of cholesterol homeostasis markers between cohorts with and without macrovascular events showed no significant differences in markers of cholesterol synthesis or absorption. Using logistic regression analysis, the odds ratio was not statistically significant for the prediction of macrovascular events after full-adjusting for age, sex, diabetes, serum albumin, cholesterol, and triglyceride. We concluded that hemodialysis patients demonstrated higher level of cholesterols absorption, indicated by circulating campesterol compared to healthy subjects. Markers for cholesterol homeostasis were not significantly associated with macrovascular events during a 1-year follow-up. Our results shed light on the novel therapeutic target of modulating cholesterol absorption in HD patients.
Topics: Aged; Biomarkers; Cholesterol; Female; Homeostasis; Humans; Logistic Models; Male; Middle Aged; Odds Ratio; Regression Analysis; Renal Dialysis; Sitosterols; Triglycerides
PubMed: 33801029
DOI: 10.3390/nu13031014