Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries and also in other parts of the world. NAFLD encompasses a histological spectrum ranging from simple steatosis to steatohepatitis, advanced fibrosis and inflammatory changes. It frequently occurs with features of the metabolic syndrome including obesity, type 2 diabetes mellitus, dyslipidemia and hypertension. In fact, the metabolic syndrome is a strong predictor of NAFLD. Recently, Niemann-Pick C1-like 1 (NPC1L1) has been shown to play a pivotal role in cholesterol absorption. Unlike mouse NPC1L1 protein, predominantly expressed in the intestines, human and rat NPC1L1 is also abundantly expressed in the liver. Though the exact functions of hepatic NPC1L1 remain unknown, NPC1L1 may facilitate the hepatic accumulation of cholesterol. This raises a potential possibility that ezetimibe may improve fatty liver formation. In this review, potential role of lipid metabolism in NAFLD and its possible modulation through NPC1L1 blockade is discussed.
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PMID:Novel role of NPC1L1 in the regulation of hepatic metabolism: potential contribution of ezetimibe in NAFLD/NASH treatment. 2104 16

We recently reported that lecithin:cholesterol acyltransferase (LCAT) knock-out mice, particularly in the LDL receptor knock-out background, are hypersensitive to insulin and resistant to high fat diet-induced insulin resistance (IR) and obesity. We demonstrated that chow-fed Ldlr-/-xLcat+/+ mice have elevated hepatic endoplasmic reticulum (ER) stress, which promotes IR, compared with wild-type controls, and this effect is normalized in Ldlr-/-xLcat-/- mice. In the present study, we tested the hypothesis that hepatic ER cholesterol metabolism differentially regulates ER stress using these models. We observed that the Ldlr-/-xLcat+/+ mice accumulate excess hepatic total and ER cholesterol primarily attributed to increased reuptake of biliary cholesterol as we observed reduced biliary cholesterol in conjunction with decreased hepatic Abcg5/g8 mRNA, increased Npc1l1 mRNA, and decreased Hmgr mRNA and nuclear SREBP2 protein. Intestinal NPC1L1 protein was induced. Expression of these genes was reversed in the Ldlr-/-xLcat-/- mice, accounting for the normalization of total and ER cholesterol and ER stress. Upon feeding a 2% high cholesterol diet (HCD), Ldlr-/-xLcat-/- mice accumulated a similar amount of total hepatic cholesterol compared with the Ldlr-/-xLcat+/+ mice, but the hepatic ER cholesterol levels remained low in conjunction with being protected from HCD-induced ER stress and IR. Hepatic ER stress correlates strongly with hepatic ER free cholesterol but poorly with hepatic tissue free cholesterol. The unexpectedly low ER cholesterol seen in HCD-fed Ldlr-/-xLcat-/- mice was attributable to a coordinated marked up-regulation of ACAT2 and suppressed SREBP2 processing. Thus, factors influencing the accumulation of ER cholesterol may be important for the development of hepatic insulin resistance.
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PMID:Lecithin:cholesterol acyltransferase deficiency protects against cholesterol-induced hepatic endoplasmic reticulum stress in mice. 2250 17