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Comprehensive Physiology Jul 2013Bile acids are important physiological agents for intestinal nutrient absorption and biliary secretion of lipids, toxic metabolites, and xenobiotics. Bile acids also are... (Review)
Review
Bile acids are important physiological agents for intestinal nutrient absorption and biliary secretion of lipids, toxic metabolites, and xenobiotics. Bile acids also are signaling molecules and metabolic regulators that activate nuclear receptors and G protein-coupled receptor (GPCR) signaling to regulate hepatic lipid, glucose, and energy homeostasis and maintain metabolic homeostasis. Conversion of cholesterol to bile acids is critical for maintaining cholesterol homeostasis and preventing accumulation of cholesterol, triglycerides, and toxic metabolites, and injury in the liver and other organs. Enterohepatic circulation of bile acids from the liver to intestine and back to the liver plays a central role in nutrient absorption and distribution, and metabolic regulation and homeostasis. This physiological process is regulated by a complex membrane transport system in the liver and intestine regulated by nuclear receptors. Toxic bile acids may cause inflammation, apoptosis, and cell death. On the other hand, bile acid-activated nuclear and GPCR signaling protects against inflammation in liver, intestine, and macrophages. Disorders in bile acid metabolism cause cholestatic liver diseases, dyslipidemia, fatty liver diseases, cardiovascular diseases, and diabetes. Bile acids, bile acid derivatives, and bile acid sequestrants are therapeutic agents for treating chronic liver diseases, obesity, and diabetes in humans.
Topics: Animals; Bile Acids and Salts; Biliary Tract Diseases; Cholesterol; Enterohepatic Circulation; Feedback, Physiological; Homeostasis; Humans; Inflammation; Liver; Receptors, Cytoplasmic and Nuclear; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 23897684
DOI: 10.1002/cphy.c120023 -
Physiological Reviews Apr 2014Thyroid hormone (TH) is required for normal development as well as regulating metabolism in the adult. The thyroid hormone receptor (TR) isoforms, α and β, are... (Review)
Review
Thyroid hormone (TH) is required for normal development as well as regulating metabolism in the adult. The thyroid hormone receptor (TR) isoforms, α and β, are differentially expressed in tissues and have distinct roles in TH signaling. Local activation of thyroxine (T4), to the active form, triiodothyronine (T3), by 5'-deiodinase type 2 (D2) is a key mechanism of TH regulation of metabolism. D2 is expressed in the hypothalamus, white fat, brown adipose tissue (BAT), and skeletal muscle and is required for adaptive thermogenesis. The thyroid gland is regulated by thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH). In addition to TRH/TSH regulation by TH feedback, there is central modulation by nutritional signals, such as leptin, as well as peptides regulating appetite. The nutrient status of the cell provides feedback on TH signaling pathways through epigentic modification of histones. Integration of TH signaling with the adrenergic nervous system occurs peripherally, in liver, white fat, and BAT, but also centrally, in the hypothalamus. TR regulates cholesterol and carbohydrate metabolism through direct actions on gene expression as well as cross-talk with other nuclear receptors, including peroxisome proliferator-activated receptor (PPAR), liver X receptor (LXR), and bile acid signaling pathways. TH modulates hepatic insulin sensitivity, especially important for the suppression of hepatic gluconeogenesis. The role of TH in regulating metabolic pathways has led to several new therapeutic targets for metabolic disorders. Understanding the mechanisms and interactions of the various TH signaling pathways in metabolism will improve our likelihood of identifying effective and selective targets.
Topics: Animals; Body Weight; Carbohydrate Metabolism; Cholesterol; Energy Metabolism; Humans; Signal Transduction; Thermogenesis; Thyroid Gland; Thyroid Hormones; Triglycerides
PubMed: 24692351
DOI: 10.1152/physrev.00030.2013 -
Signal Transduction and Targeted Therapy Aug 2022Disturbed cholesterol homeostasis plays critical roles in the development of multiple diseases, such as cardiovascular diseases (CVD), neurodegenerative diseases and... (Review)
Review
Disturbed cholesterol homeostasis plays critical roles in the development of multiple diseases, such as cardiovascular diseases (CVD), neurodegenerative diseases and cancers, particularly the CVD in which the accumulation of lipids (mainly the cholesteryl esters) within macrophage/foam cells underneath the endothelial layer drives the formation of atherosclerotic lesions eventually. More and more studies have shown that lowering cholesterol level, especially low-density lipoprotein cholesterol level, protects cardiovascular system and prevents cardiovascular events effectively. Maintaining cholesterol homeostasis is determined by cholesterol biosynthesis, uptake, efflux, transport, storage, utilization, and/or excretion. All the processes should be precisely controlled by the multiple regulatory pathways. Based on the regulation of cholesterol homeostasis, many interventions have been developed to lower cholesterol by inhibiting cholesterol biosynthesis and uptake or enhancing cholesterol utilization and excretion. Herein, we summarize the historical review and research events, the current understandings of the molecular pathways playing key roles in regulating cholesterol homeostasis, and the cholesterol-lowering interventions in clinics or in preclinical studies as well as new cholesterol-lowering targets and their clinical advances. More importantly, we review and discuss the benefits of those interventions for the treatment of multiple diseases including atherosclerotic cardiovascular diseases, obesity, diabetes, nonalcoholic fatty liver disease, cancer, neurodegenerative diseases, osteoporosis and virus infection.
Topics: Atherosclerosis; Cardiovascular Diseases; Cholesterol; Foam Cells; Homeostasis; Humans
PubMed: 35918332
DOI: 10.1038/s41392-022-01125-5 -
Hepatology Communications Jan 2022The rising prevalence of nonalcoholic fatty liver disease (NAFLD) and NAFLD-related cirrhosis in the United States and globally highlights the need to better understand... (Review)
Review
The rising prevalence of nonalcoholic fatty liver disease (NAFLD) and NAFLD-related cirrhosis in the United States and globally highlights the need to better understand the mechanisms causing progression of hepatic steatosis to fibrosing steatohepatitis and cirrhosis in a small proportion of patients with NAFLD. Accumulating evidence suggests that lipotoxicity mediated by hepatic free cholesterol (FC) overload is a mechanistic driver for necroinflammation and fibrosis, characteristic of nonalcoholic steatohepatitis (NASH), in many animal models and also in some patients with NASH. Diet, lifestyle, obesity, key genetic polymorphisms, and hyperinsulinemia secondary to insulin resistance are pivotal drivers leading to aberrant cholesterol signaling, which leads to accumulation of FC within hepatocytes. FC overload in hepatocytes can lead to ER stress, mitochondrial dysfunction, development of toxic oxysterols, and cholesterol crystallization in lipid droplets, which in turn lead to hepatocyte apoptosis, necrosis, or pyroptosis. Activation of Kupffer cells and hepatic stellate cells by hepatocyte signaling and cholesterol loading contributes to this inflammation and leads to hepatic fibrosis. Cholesterol accumulation in hepatocytes can be readily prevented or reversed by statins. Observational studies suggest that use of statins in NASH not only decreases the substantially increased cardiovascular risk, but may ameliorate liver pathology. Conclusion: Hepatic FC loading may result in cholesterol-associated steatohepatitis and play an important role in the development and progression of NASH. Statins appear to provide significant benefit in preventing progression to NASH and NASH-cirrhosis. Randomized controlled trials are needed to demonstrate whether statins or statin/ezetimibe combination can effectively reverse steatohepatitis and liver fibrosis in patients with NASH.
Topics: Animals; Anticholesteremic Agents; Cholesterol; Cholesterol, Dietary; Ezetimibe; Fatty Liver; Homeostasis; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Non-alcoholic Fatty Liver Disease; Risk Factors
PubMed: 34558856
DOI: 10.1002/hep4.1801 -
Annual Review of Biochemistry Jun 2018Scap is a polytopic membrane protein that functions as a molecular machine to control the cholesterol content of membranes in mammalian cells. In the 21 years since our... (Review)
Review
Scap is a polytopic membrane protein that functions as a molecular machine to control the cholesterol content of membranes in mammalian cells. In the 21 years since our laboratory discovered Scap, we have learned how it binds sterol regulatory element-binding proteins (SREBPs) and transports them from the endoplasmic reticulum (ER) to the Golgi for proteolytic processing. Proteolysis releases the SREBP transcription factor domains, which enter the nucleus to promote cholesterol synthesis and uptake. When cholesterol in ER membranes exceeds a threshold, the sterol binds to Scap, triggering several conformational changes that prevent the Scap-SREBP complex from leaving the ER. As a result, SREBPs are no longer processed, cholesterol synthesis and uptake are repressed, and cholesterol homeostasis is restored. This review focuses on the four domains of Scap that undergo concerted conformational changes in response to cholesterol binding. The data provide a molecular mechanism for the control of lipids in cell membranes.
Topics: Animals; Cholesterol; Homeostasis; Humans; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Models, Biological; Models, Molecular; Protein Conformation; Protein Transport; Proteolysis; Receptors, LDL; Sterol Regulatory Element Binding Proteins
PubMed: 28841344
DOI: 10.1146/annurev-biochem-062917-011852 -
Nutrients Jul 2020Cholesterol, the most important sterol in mammals, helps maintain plasma membrane fluidity and is a precursor of bile acids, oxysterols, and steroid hormones.... (Review)
Review
Cholesterol, the most important sterol in mammals, helps maintain plasma membrane fluidity and is a precursor of bile acids, oxysterols, and steroid hormones. Cholesterol in the body is obtained from the diet or can be de novo synthetized. Cholesterol homeostasis is mainly regulated by the liver, where cholesterol is packed in lipoproteins for transport through a tightly regulated process. Changes in circulating lipoprotein cholesterol levels lead to atherosclerosis development, which is initiated by an accumulation of modified lipoproteins in the subendothelial space; this induces significant changes in immune cell differentiation and function. Beyond lesions, cholesterol levels also play important roles in immune cells such as monocyte priming, neutrophil activation, hematopoietic stem cell mobilization, and enhanced T cell production. In addition, changes in cholesterol intracellular metabolic enzymes or transporters in immune cells affect their signaling and phenotype differentiation, which can impact on atherosclerosis development. In this review, we describe the main regulatory pathways and mechanisms of cholesterol metabolism and how these affect immune cell generation, proliferation, activation, and signaling in the context of atherosclerosis.
Topics: Animals; Atherosclerosis; Cell Proliferation; Cholesterol; Hematopoiesis; Homeostasis; Humans; Immunity, Cellular; Lipid Metabolism; Lipoproteins; Liver; Macrophages; Mice; Monocytes; Neutrophils; T-Lymphocytes
PubMed: 32645995
DOI: 10.3390/nu12072021 -
Nature Reviews. Endocrinology Aug 2018Liver X receptors α and β (LXRα and LXRβ) are nuclear receptors with pivotal roles in the transcriptional control of lipid metabolism. Transcriptional activity of... (Review)
Review
Liver X receptors α and β (LXRα and LXRβ) are nuclear receptors with pivotal roles in the transcriptional control of lipid metabolism. Transcriptional activity of LXRs is induced in response to elevated cellular levels of cholesterol. LXRs bind to and regulate the expression of genes that encode proteins involved in cholesterol absorption, transport, efflux, excretion and conversion to bile acids. The coordinated, tissue-specific actions of the LXR pathway maintain systemic cholesterol homeostasis and regulate immune and inflammatory responses. LXRs also regulate fatty acid metabolism by controlling the lipogenic transcription factor sterol regulatory element-binding protein 1c and regulate genes that encode proteins involved in fatty acid elongation and desaturation. LXRs exert important effects on the metabolism of phospholipids, which, along with cholesterol, are major constituents of cellular membranes. LXR activation preferentially drives the incorporation of polyunsaturated fatty acids into phospholipids by inducing transcription of the remodelling enzyme lysophosphatidylcholine acyltransferase 3. The ability of the LXR pathway to couple cellular sterol levels with the saturation of fatty acids in membrane phospholipids has implications for several physiological processes, including lipoprotein production, dietary lipid absorption and intestinal stem cell proliferation. Understanding how LXRs regulate membrane composition and function might provide new therapeutic insight into diseases associated with dysregulated lipid metabolism, including atherosclerosis, diabetes mellitus and cancer.
Topics: Animals; Cholesterol; Gene Expression Regulation; Homeostasis; Humans; Lipid Metabolism; Liver X Receptors; Needs Assessment; Signal Transduction; Translational Research, Biomedical
PubMed: 29904174
DOI: 10.1038/s41574-018-0037-x -
The Yale Journal of Biology and Medicine Mar 2012The LDLR family of proteins is involved in lipoproteins trafficking. While the role of LDLR in cardiovascular disease has been widely studied, only recently the role of... (Review)
Review
The LDLR family of proteins is involved in lipoproteins trafficking. While the role of LDLR in cardiovascular disease has been widely studied, only recently the role of other members of the LDLR proteins in lipoprotein homeostasis and atherosclerosis has emerged. LDLR, VLDLR, and LRPs bind and internalize apoE- and apoB-containing lipoprotein, including LDL and VLDL, and regulate their cellular uptake. LRP6 is a unique member of this family for its function as a co-receptor for Wnt signal transduction. The work in our laboratory has shown that LRP6 also plays a key role in lipoprotein and TG clearance, glucose homoeostasis, and atherosclerosis. The role of these receptor proteins in pathogenesis of diverse metabolic risk factors is emerging, rendering them targets of novel therapeutics for metabolic syndrome and atherosclerosis. This manuscript reviews the physiological role of the LDLR family of proteins and describes its involvement in pathogenesis of hyperlipidemia and atherosclerosis.
Topics: Animals; Cholesterol; Homeostasis; Humans; LDL-Receptor Related Proteins; Models, Biological; Multigene Family; Receptors, LDL
PubMed: 22461740
DOI: No ID Found -
Journal of Hepatology Feb 2019Hepatic lipid metabolism is a series of complex processes that control influx and efflux of not only hepatic lipid pools, but also organismal pools. Lipid homeostasis is... (Review)
Review
Hepatic lipid metabolism is a series of complex processes that control influx and efflux of not only hepatic lipid pools, but also organismal pools. Lipid homeostasis is usually tightly controlled by expression, substrate supply, oxidation and secretion that keep hepatic lipid pools relatively constant. However, perturbations of any of these processes can lead to lipid accumulation in the liver. Although it is thought that these responses are hepatic arms of the 'thrifty genome', they are maladaptive in the context of chronic fatty liver diseases. Ethanol is likely unique among toxins, in that it perturbs almost all aspects of hepatic lipid metabolism. This complex response is due in part to the large metabolic demand placed on the organ by alcohol metabolism, but also appears to involve more nuanced changes in expression and substrate supply. The net effect is that steatosis is a rapid response to alcohol abuse. Although transient steatosis is largely an inert pathology, the chronicity of alcohol-related liver disease seems to require steatosis. Better and more specific understanding of the mechanisms by which alcohol causes steatosis may therefore translate into targeted therapies to treat alcohol-related liver disease and/or prevent its progression.
Topics: Alcoholism; Animals; Cholesterol; Ethanol; Fatty Acid Transport Proteins; Fatty Acids; Fatty Liver, Alcoholic; Homeostasis; Humans; Mitochondria; Oxidation-Reduction; Triglycerides
PubMed: 30658725
DOI: 10.1016/j.jhep.2018.10.037 -
Nature Communications Aug 2021Hypercholesterolemia and dyslipidemia are associated with an increased risk for many cancer types and with poor outcomes in patients with established disease. Whereas...
Hypercholesterolemia and dyslipidemia are associated with an increased risk for many cancer types and with poor outcomes in patients with established disease. Whereas the mechanisms by which this occurs are multifactorial we determine that chronic exposure of cells to 27-hydroxycholesterol (27HC), an abundant circulating cholesterol metabolite, selects for cells that exhibit increased cellular uptake and/or lipid biosynthesis. These cells exhibit substantially increased tumorigenic and metastatic capacity. Notably, the metabolic stress imposed upon cells by the accumulated lipids requires sustained expression of GPX4, a negative regulator of ferroptotic cell death. We show that resistance to ferroptosis is a feature of metastatic cells and further demonstrate that GPX4 knockdown attenuates the enhanced tumorigenic and metastatic activity of 27HC resistant cells. These findings highlight the general importance of ferroptosis in tumor growth and metastasis and suggest that dyslipidemia/hypercholesterolemia impacts cancer pathogenesis by selecting for cells that are resistant to ferroptotic cell death.
Topics: Animals; Breast Neoplasms; Cell Death; Cell Line, Tumor; Cell Proliferation; Cholesterol; Female; Ferroptosis; Gene Expression Regulation, Neoplastic; Glutathione Peroxidase; Homeostasis; Humans; Hydroxycholesterols; Lipid Metabolism; Lung Neoplasms; MCF-7 Cells; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasms; Xenograft Model Antitumor Assays; Mice
PubMed: 34429409
DOI: 10.1038/s41467-021-25354-4