Showing papers by "Sandra K. Erickson published in 2002"
TL;DR: A new metabolic disorder presenting with hyperlipidemia caused by a homozygous deletion mutation in CYP7A1 is reported, which leads to a frameshift that results in loss of the active site and enzyme function.
Abstract: Bile acid synthesis plays a critical role in the maintenance of mammalian cholesterol homeostasis. The CYP7A1 gene encodes the enzyme cholesterol 7α-hydroxylase, which catalyzes the initial step in cholesterol catabolism and bile acid synthesis. We report here a new metabolic disorder presenting with hyperlipidemia caused by a homozygous deletion mutation in CYP7A1. The mutation leads to a frameshift (L413fsX414) that results in loss of the active site and enzyme function. High levels of LDL cholesterol were seen in three homozygous subjects. Analysis of a liver biopsy and stool from one of these subjects revealed double the normal hepatic cholesterol content, a markedly deficient rate of bile acid excretion, and evidence for upregulation of the alternative bile acid pathway. Two male subjects studied had hypertriglyceridemia and premature gallstone disease, and their LDL cholesterol levels were noticeably resistant to 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. One subject also had premature coronary and peripheral vascular disease. Study of the kindred, which is of English and Celtic background, revealed that individuals heterozygous for the mutation are also hyperlipidemic, indicating that this is a codominant disorder.
510 citations
TL;DR: A mechanism through which insulin signaling regulates insulin sensitivity by modulating hepatic insulin clearance is suggested by suggesting that CEACAM1 phosphorylation leads to upregulation of receptor-mediated insulin endocytosis and degradation in the hepatocyte.
Abstract: We hypothesized that insulin stimulates phosphorylation of CEACAM1 which in turn leads to upregulation of receptor-mediated insulin endocytosis and degradation in the hepatocyte. We have generated transgenic mice over-expressing in liver a dominant-negative, phosphorylation-defective S503A-CEACAM1 mutant. Supporting our hypothesis, we found that S503A-CEACAM1 transgenic mice developed hyperinsulinemia resulting from impaired insulin clearance. The hyperinsulinemia caused secondary insulin resistance with impaired glucose tolerance and random, but not fasting, hyperglycemia. Transgenic mice developed visceral adiposity with increased amounts of plasma free fatty acids and plasma and hepatic triglycerides. These findings suggest a mechanism through which insulin signaling regulates insulin sensitivity by modulating hepatic insulin clearance.
250 citations
TL;DR: Both hydrophobic and hydrophilic bile acids are effective in maintaining FXR mRNA and nuclear protein levels, however, the activating ligand in the enterohepatic flux is necessary for FXR-mediated transcriptional regulation, which leads to down-regulation of CYP7A1.
37 citations
TL;DR: The effects of apoE deficiency reflect events at the level of the adrenal gland and are specific to changes in cholesterol accumulation and corticosterone production, and support the hypothesis that apOE acts to enhance adrenocortical EC accumulation and diminish corticosteroid production.
22 citations
Journal Article•
TL;DR: A new metabolic disorder presenting with hyperlipidemia caused by a homozygous deletion mutation in CYP7A1 is reported, which leads to a frameshift that results in loss of the active site and enzyme function.
Abstract: Bile acid synthesis plays a critical role in the maintenance of mammalian cholesterol homeostasis. The CYP7A1 gene encodes the enzyme cholesterol 7α-hydroxylase, which catalyzes the initial step in cholesterol catabolism and bile acid synthesis. We report here a new metabolic disorder presenting with hyperlipidemia caused by a homozygous deletion mutation in CYP7A1. The mutation leads to a frameshift (L413fsX414) that results in loss of the active site and enzyme function. High levels of LDL cholesterol were seen in three homozygous subjects. Analysis of a liver biopsy and stool from one of these subjects revealed double the normal hepatic cholesterol content, a markedly deficient rate of bile acid excretion, and evidence for upregulation of the alternative bile acid pathway. Two male subjects studied had hypertriglyceridemia and premature gallstone disease, and their LDL cholesterol levels were noticeably resistant to 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. One subject also had premature coronary and peripheral vascular disease. Study of the kindred, which is of English and Celtic background, revealed that individuals heterozygous for the mutation are also hyperlipidemic, indicating that this is a codominant disorder.
7 citations