title: Ezetimibe markedly attenuates hepatic cholesterol accumulation and improves liver function in the lysosomal acid lipase-deficient mouse, a model for cholesteryl ester storage disease.
abstract: Lysosomal acid lipase (LAL) plays a critical role in the intracellular handling of lipids by hydrolyzing cholesteryl esters (CE) and triacylglycerols (TAG) contained in newly internalized lipoproteins. In humans, mutations in the LAL gene result in cholesteryl ester storage disease (CESD), or in Wolman disease (WD) when the mutations cause complete loss of LAL activity. A rat model for WD and a mouse model for CESD have been described. In these studies we used LAL-deficient mice to investigate how modulating the amount of intestinally-derived cholesterol reaching the liver might impact its mass, cholesterol content, and function in this model. The main experiment tested if ezetimibe, a potent cholesterol absorption inhibitor, had any effect on CE accumulation in mice lacking LAL. In male Lal(-/-) mice given ezetimibe in their diet (20 mg/day/kg bw) for 4 weeks starting at 21 days of age, both liver mass and hepatic cholesterol concentration (mg/g) were reduced to the extent that whole-liver cholesterol content (mg/organ) in the treated mice (74.3±3.4) was only 56% of that in those not given ezetimibe (133.5±6.7). There was also a marked improvement in plasma alanine aminotransferase (ALT) activity. Thus, minimizing cholesterol absorption has a favorable impact on the liver in CESD.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9151, United States. Electronic address: jen-chieh.chuang@utsouthwestern.edu.
authors.forename: Jen-Chieh
authors.initials: JC
authors.lastname: Chuang
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9151, United States. Electronic address: adam.lopez@utsouthwestern.edu.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Lopez
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9151, United States. Electronic address: kenneth.posey@utsouthwestern.edu.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Posey
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9151, United States. Electronic address: stephen.turley@utsouthwestern.edu.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Turley
mesh_terms: D000818:Animals; D001384:Azetidines / Q000494:pharmacology / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol; D015217:Cholesterol Ester Storage Disease / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D000069438:Ezetimibe; D006529:Hepatomegaly / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D002787:Sterol Esterase / Q000172:deficiency* / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: D001384:Azetidines; D014280:Triglycerides; D002784:Cholesterol; D002787:Sterol Esterase; C505054:lysosomal acid lipase, mouse; D000069438:Ezetimibe
keywords: ALT; CE; Cholesterol absorption; Fatty liver; Hepatomegaly; Intrahepatic; LAL; LIPA; NPC1L1; Niemann-Pick C1-Like1; SI; Small intestine; TAG; Triacylglycerol; UC; alanine aminotransferase; cholesteryl ester; gene that encodes LAL; lysosomal acid lipase; small intestine; triacylglycerol; unesterified cholesterol