PDZK1 is a four-PDZ domain-containing scaffold protein that, via its first PDZ domain (PDZ1), binds to the C terminus of the high density lipoprotein (HDL) receptor scavenger receptor, class B, type I (SR-BI). Abolishing PDZK1 expression in PDZK1 knock-out (KO) mice leads to a post-transcriptional, tissue-specific decrease in SR-BI protein level and an increase in total plasma cholesterol carried in abnormally large HDL particles. Here we show that, although hepatic overexpression of PDZK1 restored normal SR-BI protein abundance and function in PDZK1 KO mice, hepatic overexpression of only the PDZ1 domain was not sufficient to restore normal SR-BI function. In wild-type mice, overexpression of the PDZ1 domain overcame the activity of the endogenous hepatic PDZK1, resulting in a 75% reduction in hepatic SR-BI protein levels and intracellular mislocalization of the remaining SR-BI. As a consequence, the plasma lipoproteins in PDZ1 transgenic mice resembled those in PDZK1 KO mice (hypercholesterolemia due to large HDL). These results indicate that the PDZ1 domain can control the abundance and localization, and therefore the function, of hepatic SR-BI and that structural features of PDZK1 in addition to its SR-BI-binding PDZ1 domain are required for normal hepatic SR-BI regulation.The high density lipoprotein (HDL) 3 receptor SR-BI (scavenger receptor, class B, type I) plays a key role in lipoprotein metabolism (1) by mediating the cellular uptake of cholesteryl esters from HDL and other lipoproteins into cells (2-7) via a mechanism called selective lipid uptake (3, 8 -10). SR-BI also mediates bidirectional flux of unesterified cholesterol between cells and lipoproteins (11)(12)(13)(14).Most in vivo analyses of the physiological function of SR-BI have been conducted in mice. SR-BI is highly expressed in the liver and steroidogenic tissues (adrenal gland, ovary, and testis), which exhibit the highest levels of HDL cholesterol uptake (3). Experimental manipulations of murine SR-BI expression (e.g. hepatic overexpression, homozygous null gene knock-out) can lead to changes in total plasma cholesterol levels, the ratio of plasma unesterified to total cholesterol, HDL structure, biliary cholesterol secretion, the amounts of cholesterol stored in steroidogenic tissues, and susceptibility to atherosclerosis (15-27). Homozygous null SR-BI knock-out mice exhibit abnormally elevated (ϳ2.2-fold) plasma cholesterol in large HDL particles with a unesterified cholesterol/total cholesterol ratio roughly double that of wild-type (WT) mice (19,52). This dyslipidemia is associated with female infertility and defects in the maturation and/or structure as well as reductions in the survival times of red blood cells (21,28,29,30).To date, only one intracellular protein has been shown to interact directly with and influence the function of SR-BI (31). This protein, PDZK1, regulates SR-BI expression in a tissuespecific, post-transcriptional manner (32). PDZK1 is a scaffold protein containing four PDZ protein interaction domains (Fig. 1A...
FOR THE WISCONSIN DIABETES REGISTRY PROJECTOBJECTIVE -To determine the risk of frequent and severe hypoglycemia and the associated demographic and clinical risk factors.RESEARCH DESIGN AND METHODS -Demographic and diabetes self-management factors were measured in 415 subjects followed prospectively for 4 -6.5 years of type 1 diabetes duration as participants in a population-based incident cohort. Blood samples were collected up to three times yearly to test glycosylated hemoglobin (GHb) levels. Reports of frequent (2-4 times/week) and severe (lost consciousness) hypoglycemia as well as other diabetes selfmanagement data were collected by questionnaires.RESULTS -Frequent hypoglycemia was common (33 and 35% of participants reported this on the 4-and 6.5-year questionnaires, respectively), whereas severe hypoglycemia occurred much less often. Better glycemic control (odds ratio [OR] 1.3 per 2% decrease in GHb, 95% CI 1.1-1.5) and more frequent self-monitored blood glucose (1.5 per blood glucose check, 1.3-1.7) were independently related to frequent hypoglycemia. The association of frequent hypoglycemia with intensive insulin therapy increased with age. Better glycemic control (1.5 per 2% decrease in GHb, 1.2-2.0) and older age were related to severe hypoglycemic reactions. No sociodemographic factors other than age increased the risk of hypoglycemia.CONCLUSIONS -Frequent hypoglycemia was common in a population representing the full range of glycemic control in the community. Intensive insulin management and blood glucose monitoring independently predicted frequent but not severe hypoglycemia. This information may be useful for updating patients such that minor changes in diabetes management might decrease the daily burden of this condition while maintaining intensive insulin therapy. Diabetes Care 24:1878 -1881, 2001H ypoglycemia is the most common acute complication of type 1 diabetes (1). Onset is usually rapid, and symptoms range from very mild to severe enough to cause brain damage or death (2,3). Results of the Diabetes Control and Complications Trial (DCCT) (4) increased emphasis on intensive insulin treatment but also drew attention to the accompanying risk of hypoglycemia with such therapy, particularly in adolescents.The frequency of and risk factors for moderate and/or severe hypoglycemia in young adults were described in studies conducted in clinic-or hospital-based samples (5-8), the DCCT (9), one national cross-sectional study from France, and a limited number of populationbased cohort studies (10 -12). From these studies, it is clear that a history of hypoglycemia (6,9,13) and intensive insulin therapy (9) is an important predictor.Findings regarding other factors such as age, sex, duration of diabetes, and glycemic control are not consistent across studies. The frequency of all levels of hypoglycemia has not been reported. Also, no large population-based cohort has been studied prospectively to determine the relationship of both intensive insulin therapy and glycemic control to frequent and severe hy...
PDZK1 is a scaffold protein containing four PDZ protein interaction domains, which bind to the carboxy termini of a number of membrane transporter proteins, including ion channels (e.g., CFTR) and cell surface receptors. One of these, the HDL receptor, scavenger receptor class B type I (SR-BI), exhibits a striking, tissue-specific dependence on PDZK1 for its expression and activity. In PDZK1 knockout (KO) mice there is a marked reduction of SR-BI protein expression (approximately 95%) in the liver, but not in steroidogenic tissues or, as we show in this report, in bone marrow- or spleen-derived macrophages, or lung-derived endothelial cells. Because of hepatic SR-BI deficiency, PDZK1 KO mice exhibit dyslipidemia characterized by elevated plasma cholesterol carried in abnormally large HDL particles. Here, we show that inactivation of the PDZK1 gene promotes the development of aortic root atherosclerosis in apolipoprotein E (apoE) KO mice fed with a high fat/high cholesterol diet. However, unlike complete SR-BI-deficiency in SR-BI/apoE double KO mice, PDZK1 deficiency in PDZK1/apoE double knockout mice did not result in development of occlusive coronary artery disease or myocardial infarction, presumably because of their residual expression of SR-BI. These findings demonstrate that deficiency of an adaptor protein essential for normal expression of a lipoprotein receptor promotes atherosclerosis in a murine model. They also define PDZK1 as a member of the family of proteins that is instrumental in preventing cardiovascular disease by maintaining normal lipoprotein metabolism.
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