Geniposide Improves Cholesterol Homeostasis by Regulating FXR-Mediated Liver-Gut Crosstalk of Bile Acids

2019 ◽  
Author(s):  
Jinxin Liu ◽  
Yan Li ◽  
Haiou Pan ◽  
Mingcong Fan ◽  
Lamei Xue ◽  
...  
Keyword(s):  
Bile Acids ◽  
Cholesterol Homeostasis

scholarly journals Regulation of Bile Acid and Cholesterol Metabolism by PPARs

PPAR Research ◽  
2009 ◽  
Vol 2009 ◽  
pp. 1-15 ◽  
Author(s):  
Tiangang Li ◽  
John Y. L. Chiang
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Cholesterol Metabolism ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Cholesterol Homeostasis ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Major Pathway ◽  
Therapeutic Implications

Bile acids are amphipathic molecules synthesized from cholesterol in the liver. Bile acid synthesis is a major pathway for hepatic cholesterol catabolism. Bile acid synthesis generates bile flow which is important for biliary secretion of free cholesterol, endogenous metabolites, and xenobiotics. Bile acids are biological detergents that facilitate intestinal absorption of lipids and fat-soluble vitamins. Recent studies suggest that bile acids are important metabolic regulators of lipid, glucose, and energy homeostasis. Agonists of peroxisome proliferator-activated receptors (PPARα, PPARγ, PPARδ) regulate lipoprotein metabolism, fatty acid oxidation, glucose homeostasis and inflammation, and therefore are used as anti-diabetic drugs for treatment of dyslipidemia and insulin insistence. Recent studies have shown that activation of PPARαalters bile acid synthesis, conjugation, and transport, and also cholesterol synthesis, absorption and reverse cholesterol transport. This review will focus on the roles of PPARs in the regulation of pathways in bile acid and cholesterol homeostasis, and the therapeutic implications of using PPAR agonists for the treatment of metabolic syndrome.

III. Bile acids and nuclear receptors

2003 ◽  
Vol 284 (3) ◽  
pp. G349-G356 ◽  
Author(s):  
John Y. L. Chiang
Keyword(s):  
Bile Acid ◽  
Cardiovascular Diseases ◽  
Bile Acids ◽  
Nuclear Receptors ◽  
Molecular Mechanisms ◽  
Genetic Manipulation ◽  
Regulatory Genes ◽  
Cholesterol Homeostasis ◽  
Physiological Pathways ◽  
Bile Acid Receptor

Bile acids are physiological detergents that facilitate excretion, absorption, and transport of fats and sterols in the intestine and liver. Recent studies reveal that bile acids also are signaling molecules that activate several nuclear receptors and regulate many physiological pathways and processes to maintain bile acid and cholesterol homeostasis. Mutations of the principal regulatory genes in bile acid biosynthetic pathways have recently been identified in human patients with hepatobiliary and cardiovascular diseases. Genetic manipulation of key regulatory genes and bile acid receptor genes in mice have been obtained. These advances have greatly improved our understanding of the molecular mechanisms underlying complex liver physiology but also raise many questions and controversies to be resolved. These developments will lead to early diagnosis and discovery of drugs for treatment of liver and cardiovascular diseases.

scholarly journals Gut Microbiota Dysbiosis Is Associated with Elevated Bile Acids in Parkinson’s Disease

Metabolites ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 29
Author(s):  
Peipei Li ◽  
Bryan A. Killinger ◽  
Elizabeth Ensink ◽  
Ian Beddows ◽  
Ali Yilmaz ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lipid Metabolism ◽  
Bile Acid ◽  
Gut Microbiota ◽  
Bile Acids ◽  
Lithocholic Acid ◽  
Acid Synthesis ◽  
Cholesterol Homeostasis ◽  
Secondary Bile Acid

The gut microbiome can impact brain health and is altered in Parkinson’s disease (PD). The vermiform appendix is a lymphoid tissue in the cecum implicated in the storage and regulation of the gut microbiota. We sought to determine whether the appendix microbiome is altered in PD and to analyze the biological consequences of the microbial alterations. We investigated the changes in the functional microbiota in the appendix of PD patients relative to controls (n = 12 PD, 16 C) by metatranscriptomic analysis. We found microbial dysbiosis affecting lipid metabolism, including an upregulation of bacteria responsible for secondary bile acid synthesis. We then quantitatively measure changes in bile acid abundance in PD relative to the controls in the appendix (n = 15 PD, 12 C) and ileum (n = 20 PD, 20 C). Bile acid analysis in the PD appendix reveals an increase in hydrophobic and secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA). Further proteomic and transcriptomic analysis in the appendix and ileum corroborated these findings, highlighting changes in the PD gut that are consistent with a disruption in bile acid control, including alterations in mediators of cholesterol homeostasis and lipid metabolism. Microbially derived toxic bile acids are heightened in PD, which suggests biliary abnormalities may play a role in PD pathogenesis.

Transport of bile acids in hepatic and non-hepatic tissues

2001 ◽  
Vol 204 (10) ◽  
pp. 1673-1686 ◽  
Author(s):  
M.V. St-Pierre ◽  
G.A. Kullak-Ublick ◽  
B. Hagenbuch ◽  
P.J. Meier
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Organic Anion ◽  
Cholesterol Homeostasis ◽  
Dietary Fats ◽  
Substrate Specificities ◽  
Molecular Defects ◽  
Biliary Epithelium ◽  
Bile Acid Transporters ◽  
Molecular Signals

Bile acids are steroidal amphipathic molecules derived from the catabolism of cholesterol. They modulate bile flow and lipid secretion, are essential for the absorption of dietary fats and vitamins, and have been implicated in the regulation of all the key enzymes involved in cholesterol homeostasis. Bile acids recirculate through the liver, bile ducts, small intestine and portal vein to form an enterohepatic circuit. They exist as anions at physiological pH and, consequently, require a carrier for transport across the membranes of the enterohepatic tissues. Individual bile acid carriers have now been cloned from several species. Na(+)-dependent transporters that mediate uptake into hepatocytes and reabsorption from the intestine and biliary epithelium and an ATP-dependent transporter that pumps bile acids into bile comprise the classes of transporter that are specific for bile acids. In addition, at least four human and five rat genes that code for Na(+)-independent organic anion carriers with broad multi-substrate specificities that include bile acids have been discovered. Studies concerning the regulation of these carriers have permitted identification of molecular signals that dictate eventual changes in the uptake or excretion of bile acids, which in turn have profound physiological implications. This overview summarizes and compares all known bile acid transporters and highlights findings that have identified diseases linked to molecular defects in these carriers. Recent advances that have fostered a more complete appreciation for the elaborate disposition of bile acids in humans are emphasized.

scholarly journals Human liver cholesteryl ester hydrolase: cloning, molecular characterization, and role in cellular cholesterol homeostasis

2005 ◽  
Vol 23 (3) ◽  
pp. 304-310 ◽  
Author(s):  
Bin Zhao ◽  
Ramesh Natarajan ◽  
Shobha Ghosh
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Human Liver ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Human Hepatocytes ◽  
Cholesterol Homeostasis ◽  
Cholesteryl Esters ◽  
Ester Hydrolase ◽  
Hydrolysis Of

The liver regulates cholesterol homeostasis and eliminates excess cholesterol as bile acids or biliary cholesterol. Free cholesterol for bile acid synthesis or biliary secretion is obtained by the hydrolysis of stored cholesteryl esters or from cholesteryl esters taken up by the liver from high-density lipoproteins via a selective uptake pathway. The present study was undertaken to characterize the enzyme catalyzing this reaction, namely, cholesterol ester hydrolase (CEH) from the human liver, and demonstrate its role in regulating bile acid synthesis. Two cDNAs were isolated from the human liver that differed only in the presence of an additional alanine at position 18 in one of the clones. Transient transfection of COS-7 cells with a eukaryotic expression vector containing either of these two cDNAs resulted in significant increase in the hydrolysis of cholesteryl esters, authenticating these clones as human liver CEH. CEH mRNA and protein expression in human hepatocytes were demonstrated by real-time PCR and Western blot analyses, respectively, confirming the location of this enzyme in the cell type involved in hepatic cholesterol homeostasis. Overexpression of these CEH clones in human hepatocytes resulted in significant increase in bile acid synthesis, demonstrating a role for liver CEH in modulating bile acid synthesis. This CEH gene mapped on human chromosome 16, and the two clones represent two different transcript variants resulting from splice shifts at exon 1. In conclusion, these data identify that human liver CEH was expressed in hepatocytes, where it potentially regulates the synthesis of bile acids and thus the removal of cholesterol from the body.

Nuclear receptors, bile acids and cholesterol homeostasis series – Bile acids and pregnancy

2013 ◽  
Vol 368 (1-2) ◽  
pp. 120-128 ◽  
Author(s):  
Shadi Abu-Hayyeh ◽  
Georgia Papacleovoulou ◽  
Catherine Williamson
Keyword(s):  
Bile Acids ◽  
Nuclear Receptors ◽  
Cholesterol Homeostasis

scholarly journals Cis- and Trans-Palmitoleic Acid Isomers Regulate Cholesterol Metabolism in Different Ways

2020 ◽  
Vol 11 ◽  
Author(s):  
Wen-wen Huang ◽  
Bi-hong Hong ◽  
Kai-kai Bai ◽  
Ran Tan ◽  
Ting Yang ◽  
...  
Keyword(s):  
Bile Acids ◽  
Palmitoleic Acid ◽  
Cholesterol Metabolism ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Cholesterol Absorption ◽  
Cholesterol Homeostasis ◽  
High Dose ◽  
Intestinal Cholesterol Absorption ◽  
Preventable Risk Factor

Hypercholesterolemia is a preventable risk factor for atherosclerosis and cardiovascular disease. However, the mechanisms whereby cis-palmitoleic acid (cPOA) and trans-palmitoleic acid (tPOA) promote cholesterol homeostasis and ameliorate hypercholesterolemia remain elusive. To investigate the effects of cPOA and tPOA on cholesterol metabolism and its mechanisms, we induced hypercholesterolemia in mice using a high-fat diet and then intragastrically administered cPOA or tPOA once daily for 4 weeks. tPOA administration reduced serum cholesterol, low-density lipoprotein, high-density lipoprotein, and hepatic free cholesterol and total bile acids (TBAs). Conversely, cPOA had no effect on these parameters except for TBAs. Histological examination of the liver, however, revealed that cPOA ameliorated hepatic steatosis more effectively than tPOA. tPOA significantly reduced the expression of 3-hydroxy-3-methyl glutaryl coenzyme reductase (HMGCR), LXRα, and intestinal Niemann-Pick C1-Like 1 (NPC1L1) and increased cholesterol 7-alpha hydroxylase (CYP7A1) in the liver, whereas cPOA reduced the expression of HMGCR and CYP7A1 in the liver and had no effect on intestinal NPC1L1. In summary, our results suggest that cPOA and tPOA reduce cholesterol synthesis by decreasing HMGCR levels. Furthermore, tPOA, but not cPOA, inhibited intestinal cholesterol absorption by downregulating NPC1L1. Both high-dose tPOA and cPOA may promote the conversion of cholesterol into bile acids by upregulating CYP7A1. tPOA and cPOA prevent hypercholesterolemia via distinct mechanisms.

scholarly journals The Role of the Enterohepatic Circulation of Bile Salts and Nuclear Hormone Receptors in the Regulation of Cholesterol Homeostasis: Bile Salts as Ligands for Nuclear Hormone Receptors

2003 ◽  
Vol 17 (4) ◽  
pp. 265-271 ◽  
Author(s):  
Richard N Redinger
Keyword(s):  
Bile Acid ◽  
Bile Salt ◽  
Bile Acids ◽  
Bile Salts ◽  
Hormone Receptors ◽  
Enterohepatic Circulation ◽  
Retinoid X Receptor ◽  
Cholesterol Homeostasis ◽  
Nuclear Hormone Receptors ◽  
Salt Toxicity

The coordinated effect of lipid activated nuclear hormone receptors; liver X receptor (LXR), bound by oxysterol ligands and farnesoid X receptor (FXR), bound by bile acid ligands, act as genetic transcription factors to cause feed-forward cholesterol catabolism to bile acids and feedback repression of bile acid synthesis, respectively. It is the coordinated action of LXR and FXR, each dimerized to retinoid X receptor, that signal nuclear DNA response elements to encode proteins that prevent excessive cholesterol accumulation and bile salt toxicity, respectively. LXR helps prevent hypercholesterolemia by enhancing transporters for cholesterol efflux that enhance reverse cholesterol transport, while FXR enhances intestinal reabsorption and preservation of bile salts by increasing the ileal bile acid binding protein. FXR also targets sodium taurocholate cotransport peptide and bile salt export pump (protein) genes to limit bile salt uptake and enhance export, respectively, which prevents bile salt toxicity. Other nuclear hormone receptors such as pregnan X receptor, which share the obligate partner, retinoid X receptor, and vitamin D receptor also function as bile acid sensors to signal detoxification by hydroxylation of toxic bile acids. Pharmacologically targeted receptor agonists (or antagonists) may be developed that alter cholesterol and bile salt concentrations by modulating nuclear hormone receptors and/or their coactivators or corepressors to positively affect cholesterol homeostasis and bile salt metabolism. It is the coordinated transcription factor action of LXR, which responds to ligand binding of circulating oxysterols in both liver and peripheral tissues, and FXR responding to bile salts within the enterohepatic circulation that make possible the regulation of cholesterol and bile acid homeostasis.

scholarly journals Obesity diabetes and the role of bile acids in metabolism

2016 ◽  
Vol 4 (2) ◽  
pp. 73-80 ◽  
Author(s):  
Gerald H. Tomkin ◽  
Daphne Owens
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Acid Metabolism ◽  
Cholesterol Homeostasis ◽  
Bile Acid Metabolism ◽  
Forkhead Transcription Factor ◽  
Obesity And Diabetes ◽  
Glucagon Like Peptide 1 ◽  
Fat Soluble Vitamins

AbstractBile acids have many activities over and above their primary function in aiding absorption of fat and fat soluble vitamins. Bile acids are synthesized from cholesterol, and thus are involved in cholesterol homeostasis. Bile acids stimulate glucagon-like peptide 1 (GLP1) production in the distal small bowel and colon, stimulating insulin secretion, and therefore, are involved in carbohydrate and fat metabolism. Bile acids through their insulin sensitising effect play a part in insulin resistance and type 2 diabetes. Bile acid metabolism is altered in obesity and diabetes. Both dietary restriction and weight loss due to bariatric surgery, alter the lipid carbohydrate and bile acid metabolism. Recent research suggests that the forkhead transcription factor FOXO is a central regulator of bile, lipid, and carbohydrate metabolism, but conflicting studies mean that our understanding of the complexity is not yet complete.

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