Wu Justina E, Basso Federica, Shamburek Robert D, Amar Marcelo J A, Vaisman Boris, Szakacs Gergely, Joyce Charles, Tansey Terese, Freeman Lita, Paigen Beverly J, Thomas Fairwell, Brewer H Bryan, Santamarina-Fojo Silvia
Molecular Disease Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Biol Chem. 2004 May 28;279(22):22913-25. doi: 10.1074/jbc.M402838200. Epub 2004 Mar 25.
The individual roles of hepatic versus intestinal ABCG5 and ABCG8 in sterol transport have not yet been investigated. To determine the specific contribution of liver ABCG5/G8 to sterol transport and atherosclerosis, we generated transgenic mice that overexpress human ABCG5 and ABCG8 in the liver but not intestine (liver G5/G8-Tg) in three different genetic backgrounds: C57Bl/6, apoE-KO, and low density lipoprotein receptor (LDLr)-KO. Hepatic overexpression of ABCG5/G8 enhanced hepatobiliary secretion of cholesterol and plant sterols by 1.5-2-fold, increased the amount of intestinal cholesterol available for absorption and fecal excretion by up to 27%, and decreased the accumulation of plant sterols in plasma by approximately 25%. However, it did not alter fractional intestinal cholesterol absorption, fecal neutral sterol excretion, hepatic cholesterol concentrations, or hepatic cholesterol synthesis. Consequently, overexpression of ABCG5/G8 in only the liver had no effect on the plasma lipid profile, including cholesterol, HDL-C, and non-HDL-C, or on the development of proximal aortic atherosclerosis in C57Bl/6, apoE-KO, or LDLr-KO mice. Thus, liver ABCG5/G8 facilitate the secretion of liver sterols into bile and serve as an alternative mechanism, independent of intestinal ABCG5/G8, to protect against the accumulation of dietary plant sterols in plasma. However, in the absence of changes in fractional intestinal cholesterol absorption, increased secretion of sterols into bile induced by hepatic overexpression of ABCG5/G8 was not sufficient to alter hepatic cholesterol balance, enhance cholesterol removal from the body or to alter atherogenic risk in liver G5/G8-Tg mice. These findings demonstrate that overexpression of ABCG5/G8 in the liver profoundly alters hepatic but not intestinal sterol transport, identifying distinct roles for liver and intestinal ABCG5/G8 in modulating sterol metabolism.
肝脏与肠道中的ABCG5和ABCG8在固醇转运中的个体作用尚未得到研究。为了确定肝脏ABCG5/G8对固醇转运和动脉粥样硬化的具体贡献，我们培育了在肝脏而非肠道中过表达人ABCG5和ABCG8的转基因小鼠（肝脏G5/G8-Tg），其具有三种不同的遗传背景：C57Bl/6、载脂蛋白E基因敲除（apoE-KO）和低密度脂蛋白受体（LDLr）基因敲除。肝脏中ABCG5/G8的过表达使肝胆胆固醇和植物固醇分泌增加了1.5至2倍，使可用于吸收和粪便排泄的肠道胆固醇量增加了多达27%，并使血浆中植物固醇的积累减少了约25%。然而，它并未改变肠道胆固醇的分数吸收、粪便中性固醇排泄、肝脏胆固醇浓度或肝脏胆固醇合成。因此，仅在肝脏中过表达ABCG5/G8对C57Bl/6、apoE-KO或LDLr-KO小鼠的血浆脂质谱（包括胆固醇、高密度脂蛋白胆固醇（HDL-C）和非高密度脂蛋白胆固醇（non-HDL-C））或近端主动脉粥样硬化的发展没有影响。因此，肝脏ABCG5/G8促进肝脏固醇分泌到胆汁中，并作为一种独立于肠道ABCG5/G8的替代机制，防止膳食植物固醇在血浆中积累。然而，在肠道胆固醇分数吸收没有变化的情况下，肝脏中ABCG5/G8过表达诱导的固醇向胆汁中分泌增加不足以改变肝脏胆固醇平衡、增强胆固醇从体内的清除或改变肝脏G5/G8-Tg小鼠的动脉粥样硬化风险。这些发现表明，肝脏中ABCG5/G8的过表达深刻改变了肝脏而非肠道的固醇转运，确定了肝脏和肠道ABCG5/G8在调节固醇代谢中的不同作用。
