Gondré-Lewis Marjorie C, Petrache Horia I, Wassif Christopher A, Harries Daniel, Parsegian Adrian, Porter Forbes D, Loh Y Peng
Section on Cellular Neurobiology, National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA.
J Cell Sci. 2006 May 1;119(Pt 9):1876-85. doi: 10.1242/jcs.02906.
Cholesterol is an abundant lipid in eukaryotic membranes, implicated in numerous structural and functional capacities. Here, we have investigated the mechanism by which cholesterol affects secretory granule biogenesis in vivo using Dhcr7(-/-) and Sc5d(-/-) mouse models of the human diseases, Smith-Lemli-Opitz syndrome (SLOS) and lathosterolosis. These homozygous-recessive multiple-malformation disorders are characterized by the functional absence of one of the last two enzymes in the cholesterol biosynthetic pathway, resulting in the accumulation of precursors. Cholesterol-deficient mice exhibit a significant decrease in the numbers of secretory granules in the pancreas, pituitary and adrenal glands. Moreover, there was an increase in morphologically aberrant granules in the exocrine pancreas of Dhcr7(-/-) acinar cells. Regulated secretory pathway function was also severely diminished in these cells, but could be restored with exogenous cholesterol. Sterol precursors incorporated in artificial membranes resulted in decreased bending rigidity and intrinsic curvature compared with cholesterol, thus providing a cholesterol-mediated mechanism for normal granule budding, and an explanation for granule malformation in SLOS and lathosterolosis.
胆固醇是真核细胞膜中一种丰富的脂质，参与多种结构和功能活动。在此，我们利用人类疾病史密斯-勒米-奥皮茨综合征（SLOS）和羊毛甾醇血症的Dhcr7(-/-)和Sc5d(-/-)小鼠模型，研究了胆固醇在体内影响分泌颗粒生物发生的机制。这些纯合隐性多重畸形疾病的特征是胆固醇生物合成途径中最后两种酶之一功能缺失，导致前体物质积累。胆固醇缺乏的小鼠胰腺、垂体和肾上腺中分泌颗粒的数量显著减少。此外，Dhcr7(-/-)腺泡细胞的外分泌胰腺中形态异常的颗粒有所增加。这些细胞中受调节的分泌途径功能也严重受损，但外源性胆固醇可使其恢复。与胆固醇相比，掺入人工膜中的甾醇前体导致弯曲刚度和固有曲率降低，从而为正常颗粒出芽提供了一种胆固醇介导的机制，并解释了SLOS和羊毛甾醇血症中颗粒畸形的原因。
