The formation of chylomicrons by the intestine is important for the absorption of dietary fats and fat-soluble vitamins (e.g., retinol, a-tocopherol). Apo B plays an essential structural role in the formation of chylomicrons in the intestine as well as the VLDL in the liver. We have developed genetically modified mice that express apo B in the liver but not in the intestine. By electron microscopy, the enterocytes of these mice lacked nascent chylomicrons in the endoplasmic reticulum and Golgi apparatus. Because these mice could not form chylomicrons, the intestinal villus enterocytes were massively engorged with fat, which was contained in cytosolic lipid droplets. These mice absorbed D-xylose normally, but there was virtually no absorption of retinol palmitate or cholesterol. The levels of a-tocopherol in the plasma were extremely low. Of note, the absence of chylomicron synthesis in the intestine did not appear to have a significant effect on the plasma levels of the apo B-containing lipoproteins produced by the liver. The mice lacking intestinal apo B expression represent the first genetic model of defective absorption of fats and fat-soluble vitamins and provide a useful animal model for studying nutrition and lipoprotein metabolism. (J. Clin. Invest. 1995. 96:2932-2946

Smith-Lemli-Opitz syndrome (SLOS) is a multiple congenital malformation/intellectual disability syndrome, with clinical characteristics encompassing a wide spectrum and great variability. Elucidation of the biochemical and molecular genetic basis for the autosomal recessively inherited SLOS, specifically, understanding SLOS as a cholesterol deficiency syndrome caused by mutations in DHCR7, opened up enormous possibilities for therapeutic intervention. When cholesterol was discovered to be the activator of sonic hedgehog, cholesterol deficiency with inactivation of this developmental patterning gene was thought to be the cause of SLOS malformations, yet this explanation is overly simplistic. Still, despite these important research breakthroughs, there is no proven treatment for SLOS. Better animal models are needed to allow potential treatment testing and the study of disease pathophysiology, which is incompletely understood. Creation of human cellular models will surely be useful, especially models of brain cells. In vivo human studies are essential as well. There have only been limited natural history studies of SLOS to date. Biomarker development will be critical in facilitating clinical trials in this rare condition, since clinical phenotype may change over many years. Additional research in these and other areas is critical if we are to make headway towards ameloriating the effects of this devastating condition.

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