Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015695 (fatty liver)
 13,941 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sphingolipids are major constituents of the plasma membrane, where they are known to form lipid microdomains with cholesterol. Lipid microdomains are thought to be important not only for cellular signal transduction but also for the absorption of extracellular lipids or nutrients. Inhibition of sphingolipid biosynthesis suggested an importance for sphingolipids in fatty acid uptake via lipid microdomains. Additionally, we recently reported that the function of lipid microdomains was dynamically regulated by the sphingomyelin synthase SMS2 on the plasma membrane and that SMS2-deficient mice exhibit resistance against high-fat diet-induced increases in body weight, glucose intolerance, and fatty liver. Now, biosynthesis or metabolism of sphingolipids is thought to be involved in obesity, diabetes, and cardiovascular diseases. In this review, I focus on the functions of sphingolipids in lipid microdomains and describe their contributions to obesity and diabetes.
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PMID:Sphingolipids in lipid microdomains and obesity. 2337 21

Sphingomyelin synthase 2 (SMS2) is a promising therapeutic target for several chronic inflammation-associated diseases, including atherosclerosis, fatty liver, and insulin resistance. Herein, we report the identification of 4-benzyloxybenzo[ d]isoxazole-3-amine derivatives as potent and highly selective SMS2 inhibitors through a conformational restriction strategy. After systematic structural modifications, several compounds with high selectivity and good potency in vitro were selected for further evaluation. Compound 15w demonstrated good pharmacokinetics (oral bioavailability, F = 56%) in vivo and has an inhibitory potency against sphingomyelin synthase activity when Institute of Cancer Research mice are provided with an oral dose of this compound. In addition, compound 15w attenuated chronic inflammation significantly in db/ db mice after oral dosing for 6 weeks.
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PMID:Discovery of 4-Benzyloxybenzo[ d]isoxazole-3-amine Derivatives as Highly Selective and Orally Efficacious Human Sphingomyelin Synthase 2 Inhibitors that Reduce Chronic Inflammation in db/ db Mice. 3007 91

The interaction between natural occurring inhibitors and targeted membrane proteins could be an alternative medicinal strategy for the treatment of metabolic syndrome, notably, obesity. In this study, we identified malabaricones A-C and E (1-4) isolated from the fruits of Myristica cinnamomea King as natural inhibitors for sphingomyelin synthase (SMS), a membrane protein responsible for sphingolipid biosynthesis. Having the most promising inhibition, oral administration of compound 3 exhibited multiple efficacies in reducing weight gain, improving glucose tolerance, and reducing hepatic steatosis in high fat diet-induced obesity mice models. Liver lipid analysis revealed a crucial link between the SMS activities of compound 3 and its lipid metabolism in vitro and in vivo. The nontoxic nature of compound 3 makes it a suitable candidate in search of drugs which can be employed in the treatment and prevention of obesity.
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PMID:Malabaricone C as Natural Sphingomyelin Synthase Inhibitor against Diet-Induced Obesity and Its Lipid Metabolism in Mice. 3141 99