Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Besides their well-established roles in dietary lipid absorption and cholesterol homeostasis, bile acids (BA) also act as metabolically active signaling molecules. The flux of reabsorbed BA undergoing enterohepatic circulation, arriving in the liver with the co-absorbed nutrients (e.g. glucose, lipids), provides a signal that coordinates hepatic triglyceride (TG), glucose and energy homeostasis. As signaling molecules with systemic endocrine functions, BA can activate protein kinases A and C as well as mitogen-activated protein kinase pathways. Additionally, they are ligands for a G-protein-coupled BA receptor (TGR5/Gpbar-1) and activate nuclear receptors such as farnesoid X receptor (FXR; NR1H4). FXR and its downstream targets play a key role in the control of hepatic de novo lipogenesis, very-low-density lipoprotein-TG export and plasma TG turnover. BA-activated FXR and signal transduction pathways are also involved in the regulation of hepatic gluconeogenesis, glycogen synthesis and insulin sensitivity. Via TGR5, BA are able to stimulate glucagon-like peptide-1 secretion in the small intestine and energy expenditure in brown adipose tissue and skeletal muscle. Dysregulation of BA transport and impaired BA receptor signaling may contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Thus, BA transport and BA-controlled nuclear receptors and signaling pathways are promising drug targets for treatment of NAFLD. As such, FXR and/or TGR5 ligands have shown promising results in animal models of NAFLD and clinical pilot studies. Despite being a poor FXR and TGR5 ligand, ursodeoxycholic acid (UDCA) improves hepatic ER stress and insulin sensitivity. Notably, norUDCA, a side chain-shortened homologue of UDCA, improves fatty liver and atherosclerosis in Western diet-fed ApoE(-/-) mice. Collectively, these findings suggest that BA and targeting their receptor/signaling pathways may represent a promising approach to treat NAFLD and closely linked disorders such as obesity, diabetes, dyslipidemia and arteriosclerosis.
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PMID:Bile acids as regulators of hepatic lipid and glucose metabolism. 2046 Sep 15

Abnormally elevated lipid and glucose levels due to the disruption of metabolic homeostasis play causative roles in the development of metabolic diseases. A cluster of metabolic conditions, including dyslipidemia, abdominal obesity, and insulin resistance, is referred to as metabolic syndrome, which has been increasing globally at an alarming rate. The primary nuclear bile acid receptor, Farnesoid X Receptor (FXR, NR1H4), plays important roles in controlling lipid and glucose levels by regulating expression of target genes in response to bile acid signaling in enterohepatic tissues. In this review, I discuss how signal-dependent FXR transcriptional activity is dynamically regulated under normal physiological conditions and how it is dysregulated in metabolic disease states. I focus on the emerging roles of post-translational modifications (PTMs) and transcriptional cofactors in modulating FXR transcriptional activity and pathways. Dysregulation of nuclear receptor transcriptional signaling due to aberrant PTMs and cofactor interactions are key determinants in the development of metabolic diseases. Therefore, targeting such abnormal PTMs and transcriptional cofactors of FXR in disease states may provide a new molecular strategy for development of pharmacological agents to treat metabolic syndrome. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.
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PMID:Regulation of FXR transcriptional activity in health and disease: Emerging roles of FXR cofactors and post-translational modifications. 2113 Jan 62

This snapshot reviews the current state of knowledge on genetic variants of nuclear receptors (NRs) involved in regulating various aspects of liver metabolism. Interindividual differences in responses to diet and other 'in-' and environmental stressors can be caused by variants in components of the NR regulatory gene network. We recapitulate recent evidence for the application of NRs in genetic diagnosis of monogenic liver disease. Genetic analysis of multifactorial liver diseases, such as nonalcoholic fatty liver disease and diabetes mellitus, pinpoints key players in disease predisposition and progression. In particular, NR1H4 variants have been associated with intrahepatic cholestasis of pregnancy and gallstone disease. Other examples include studies of NR1I2 and NR1I3 polymorphisms in patients with drug-induced liver injury and NR5A2 variation in cholangiocarcinoma. Associations of NR gene variants have been identified in patients with dyslipidemia and other metabolic syndrome-associated traits by genome-wide studies. Evidence from these analyses confirms a role for NR variation in common diseases, linking regulatory networks to complex and variable phenotypes. These new insights into the impact of NR variants offer perspectives for their future use in diagnosis and treatment of common diseases.
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PMID:Nuclear receptor variants in liver disease. 2604 77