Cholesterol esterification and Niemann-Pick disease: an approach to identifying the defect in fibroblasts.

Fibroblasts from 13 patients with the clinical phenotype of type IIS, Niemann-Pick disease were evaluated for their ability to incorporate oleic acid into cholesterol esters via an LDL responsive mechanism. Eight patients displayed a severe deficiency (less than 8% of normal) of cholesterol ester (CE) synthesis while a clinically less affected group displayed intermediate levels (36% of normal) of synthetic capacity with no detectable overlap between these groups and the control range. There was no deficiency in cholesterol ester production in fibroblasts from a patient with Zellweger's disease, a disorder characterized by altered peroxisomes and abnormal peroxisomal cholesterol metabolism, while in I-cell disease, characterized by a primary deficiency of a phosphotransferase which results in altered targeting of lysosomal hydrolases, it was reduced to 25% of the control level. To further implicate lysosomal proteins in the etiology of type IIS, Niemann-Pick disease we measured the effect of correction (conditioned) medium, and the lysosomotropic agent, NH4Cl on cholesterol ester synthesis in fibroblasts. NH4Cl completely inhibited incorporation into CE by normal cells, thus mimicking the CE defect in type IIS, Niemann-Pick cells. Conditioned medium had no effect on incorporation into CE synthesis but medium conditioned in the presence of 10 mM NH4Cl stimulated incorporation into CE in the control but not in Niemann-Pick cells. When Niemann-Pick cells cultured in the presence of NH4Cl were challenged to synthesize CE in the absence of NH4Cl, a significant enhancement of CE synthesis was noted in representative cell lines from both groups of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Damage of rat liver sinusoidal endothelium by ethanol.

Hepatic blood in normal rats is separated from the space of Disse and hepatocytes by an ultrastructural sieve formed by pores in the sinusoidal endothelium. This sieve has previously been shown to shield hepatocytes from circulating chylomicrons, the largest of the lipoproteins, which transport most triglycerides of dietary origin. In the present paper it has been shown that the chronic ingestion of ethanol leads to a significant enlargement of pores within the sieve, increasing them from a normal median diameter of 100 nm to 120 nm. A decrease in the normal sieving of perfused labelled large and small chylomicrons has also been noted. It is postulated that the decreased shielding of hepatocytes from large chylomicrons may be a factor in the pathogenesis of alcoholic fatty liver.

High perfusion pressure damages the sieving ability of sinusoidal endothelium in rat livers.

Fenestrated endothelium lining liver sinusoids forms an ultrastructural sieve between blood and hepatocytes which at physiological perfusion pressures has previously been shown to shield hepatocytes from large triglyceride-rich chylomicrons. In the study reported in this paper, enlargement of endothelial fenestrae at high perfusion pressures has been confirmed and a concurrent increase in trapping of large chylomicrons by the liver noted. These findings suggest the importance of employing physiological perfusion pressures in studies designed to examine hepatic lipoprotein metabolism and also suggest a possible mechanism in the pathogenesis of fatty change seen in the "nutmeg" liver of chronic venous congestion.