Metabolic syndrome is a major risk factor for development of diabetes and coronary artery disease (CAD), two most common causes of morbidity and mortality worldwide. By genetic linkage analysis in large kindreds with autosomal dominant premature coronary artery disease (CAD), diabetes hyperlipidemia, hypertension, and osteoporosis we have identified the disease causing mutations that substitute evolutionarily highly conservative amino acids in the LDL receptor like protein (LRP6), a co-receptor in the Wnt signaling pathway. Further studies have revealed that the mutations impair the Wnt signaling and impact many component of the metabolic syndrome that is present in these kindreds. These findings have established a causal link between Wnt signaling impairment caused by LRP6 mutation and metabolic syndrome and raises the possibility of complex downstream effects of the mutation which warrant further investigation. Oral glucose tolerance tests and studies of intrahepatic fat content in LRP6 mutation carriers have indicated that the underlying cause of impaired glucose tolerance caused by LRP6 mutation is impaired insulin sensitivity. We have created a LRP6 knockout mouse to investigate physiological and cellular mechanisms of metabolic syndrome caused by LRP6 mutation in vivo. Preliminary results from IPGTT in heterozygote knockout mice on Western diet has demonstrated increased glucose stimulated insulin levels and reduced hepatic glycogen content. Reduced glycogen synthesis in the skeletal is a common heritable disorder in patients with familial type 2 diabetes. The molecular basis for inherited impaired glycogen synthesis is not well understood. GSK32 is a signal peptide that is inversely regulated by the Wnt signaling pathway. Our studies have shown that GSK32 is excessively expressed and activated in LRP6 mice tissues. GSK3 inhibits glycogen synthase activity by phosphorylation of its serine/tyrosine residues. Our goal is to study the effect of LRP6 mutation on glycogen synthase activity and glycogen synthesis in LRP6 mice and to identify the primary site of insulin resistance in this model. In additional, clinical studies in LRP6 mutation carriers suggest that the mutation may cause beta cell defect. In separate studies we will examine the insulin secretory capacity of the pancreatic islets in LRP6 mice. In addition, we will screen 60 recruited kindreds with familial early CAD, metabolic syndrome and osteoporosis for mutations in LRP6, in order to identify the spectrum and prevalence of LRP6 mutation and establish genotype-phenotype correlations.
Coronary artery disease (CAD) and the metabolic syndrome are two most common causes of morbidity and mortality in the Western world. What links the risk factors of the metabolic syndrome to each other and to coronary artery disease remains vastly unknown. We have identified the disease causing gene in several families with early coronary artery disease and metabolic syndrome. The identified disease gene (LRP6) is a co-receptor that in normal condition activates a signaling pathway known as Wnt signaling pathway. This pathway is impaired in patients who carry one of these mutations. Our finding is the first evidence for relationship between impairment of this pathway and development of CAD and metabolic syndrome in humans. The current study goals are to investigate the disease mechanisms in a mouse model of this mutation that we have created in the lab. Moreover, we plan to screen number of families with inherited CAD, metabolic syndrome, and osteoporosis for mutations within this gene to identify novel mutations and to investigate their disease causing mechanisms.
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