Hepatic triglyceride content in individuals with reduced intestinal cholesterol absorption due to variants in Nieman Pick C1-like 1.
Hepatic triglyceride content in individuals with reduced intestinal cholesterol absorption due to variants in Nieman Pick C1-like 1.
复制标题
由于 Nieman Pick C1-like 1 变异导致肠道胆固醇吸收减少的个体的肝脏甘油三酯含量。
DOI：
10.1002/hep.24461
复制
发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Browning,JeffreyD
中科院分区：
文献类型：
--
作者：
Ramirez,Ruben;Cohen,JonathanC;Hobbs,HelenH;Browning,JeffreyD
Nonalcoholic fatty liver disease (NAFLD) is a burgeoning problem in developed countries and affects up to one-third of the population. 1 NAFLD is considered to be a component of the metabolic syndrome; obesity is the primary risk factor, and weight loss and treatment of associated conditions (ie, diabetes, hyperlipidemia, among others) are the only recommended therapies. 2 Several recent studies in animal models and in humans have suggested that ezetimibe, a cholesterol-lowering agent that acts by inhibiting cholesterol absorption, may be an effective therapy for NAFLD. 3-5 The most striking and consistent finding of these small, primarily open-label studies is a significant reduction in hepatic triglyceride content. Why inhibition of intestinal cholesterol absorption should impact hepatic triglyceride metabolism is unclear. Ezetimibe acts by inhibiting Nieman Pick C1-Like 1 (NPC1L1). 6 Genetic deletion of NPC1L1 in mice decreases hepatic de novo lipogenesis. Therefore, ezetimibe may attenuate hepatic steatosis by limiting the synthesis of fatty acids in liver. 7 DNA sequencing revealed that nonsynonymous (NS) sequence variants in NPC1L1 that confer a reduced capacity for intestinal cholesterol absorption are collectively common in the population, particularly among blacks. 8, 9 Individuals who were heterozygous for one of the sequence variations in NPC1L1 had evidence of reduced sterol absoption and a 9% reduction in plasma low-density lipoprotein cholesterol. Inasmuch as these subjects represent a lifelong genetic knockdown of NPC1L1 activity, we sought to determine if they were protected from hepatic triglyceride accumulation relative to individuals with wild-type NPC1L1. The study was conducted in the Dallas Heart Study (DHS), a multiethnic population-based probability sample of Dallas County (Texas) weighted to include 50% black and 50% nonblack individuals (1043 whites, 1832 blacks, and 601 hispanics). 1 Each participant completed a 60-minute structured questionnaire that provided detailed data regarding demographics, medication use, and ethanol intake. No participant used ezetimibe. The sequencing of DNA and assays for sequence variation in NPC1L1 were previously described8 as were the methods used to determine hepatic triglyceride content. 10 The study was approved by the institutional review board (UT Southwestern), and all subjects provided written informed consent prior to participation. A total of 128 DHS participants were found to be heterozygous for one of the following NS sequence variants in NPC1L1 associated with low intestinal absorption of cholesterol: T61M, N132S, R306C, D398G, R417W, G434R, T499M, S620C, I647N, R693C, S881L, W1014X, R1108W, L110F, R306C, A395V, G402S, T413M, I647N, G672R, R693C, R1214H, or R1268H. 8 The study group was comprised 85 of these individuals (16 whites, 62 blacks, six hispanics, and one other) who had also undergone proton spectroscopy for determination of liver triglyceride content. The group included 42 women and 43 men. To determine if NS sequence variations in NPC1L1 that confer a diminished capacity for intestinal cholesterol absorption were associated with low levels of hepatic triglycerides, we compared the liver fat content of heterozygotes for these variations with the levels in a group of DHS subjects with wild-type NPC1L1 who were matched for age, race/ethnicity, sex, and body mass index. The characteristics of these groups are presented in Table 1. The two groups demonstrated no differences in serum lipid profiles, glucose concentrations, insulin sensitivity, aminotransferases, or ethanol intake. The campesterol-to-lathosterol …
