Integration of extracellular hormonal and nutrient signals into comprehensive gene expression patterns leads to tightly choreographed phenotypic responses that regulate metabolism and differentiation. My overall research interest is to determine the fundamental genetic/biochemical mechanisms that regulate glucose and lipid metabolism through the study of transcriptional and translational regulators that control energy homeostasis. The importance of genetic regulation in the maintenance of glucose homeostasis is underscored by the many examples of aberrant signal transduction and transcriptional activation resulting in type 2 diabetes and the development of secondary complications.
The regulation of fat and glucose metabolism in the liver is controlled primarily by insulin and glucagon. Changes in the circulating levels of these hormones signal fed or starvation states and elicit counter-regulatory responses that maintain normoglycemia. We have recently shown that in normal mice, plasma insulin inhibits the forkhead transcription factor Foxa2 by nuclear exclusion and that in the fasted state Foxa2 activates transcriptional programs of lipid metabolism and ketogenesis. In insulin resistant/hyperinsulinemic mice, Foxa2 is inactive and permanently located in the cytoplasm of hepatocytes. In these animals, expression of a constitutive active Foxa2 that cannot be inhibited by insulin, decreases hepatic triglyceride content, increases hepatic insulin sensitivity and normalizes plasma glucose levels through increased expression of genes encoding enzymes of fatty acid oxidation, ketogenesis and glycolysis. Future work will include studies investigating the role of Foxa2 in the central regulation of energy homeostasis, phosphorylation of Foxa2 by kinases, pharmacological screens aiming to identify small molecules that prevent phosphorylation, and identification of the Foxa2T156 phosphatase.
We have previously shown that the MODY transcription factors form a transcriptional network that is required for normal pancreatic β-cell function. We are using genetic and genomic approached to identify and characterize target genes of this transcriptional network. We have generated comprehensive gene expression profiles from mouse pancreatic islets of wildtype and transcription factors null mutants using oligonucleotide expression arrays. The analysis revealed several genes that may be involved in growth responses and differentiation processes. These genes/pathways are currently being investigated.
Beta-cell hyperplasia is an important adaptive mechanism to maintain normoglycemia during physiological growth and in obesity. Increasing evidence suggests that β-cell mass is dynamic and that increased demands on insulin secretion in insulin resistance and pregnancy can lead to rapid and marked changes in β-cell mass. The mass of β-cells is governed by the balance of β-cell growth (replication) and by β-cell death (apoptosis). However, the molecular basis of the factors that control β-cell mass remain elusive. Understanding how β-cell mass is regulated is important to design rational approaches to prevent pancreatic β-cell loss in insulin resistant states and to expand β-cells for transplantation in type 1 diabetes.
We have taken a genomic approach to identify factors that may contribute to pancreatic β-cell replication. Genome-wide gene expression analysis was performed in islets from mouse models with islet hypertrophy, reduced islet mass or physiological islet hypertrophy. Gene expression patterns were compared and genes were identified whose expression strongly correlates with islet size/β-cell numbers. We are characterizing these genes with respect to their ability to regulate islet growth, apoptosis and function.
MicroRNAs (miRNAs) are 19-22 nucleotide RNAs that regulate gene expression post-transcriptionally by base-pairing with complementary sequences in the 3' untranslated regions (UTRs) of protein-coding transcripts. This interaction leads to translational repression and in many cases to decreased mRNA levels. More than 300 human miRNAs, many of them evolutionarily conserved, are currently listed in the miRNA registry version 7.1. The total number of miRNAs encoded in the human genome is currently unclear. Computer-based predictions estimate that microRNAs constitute as many as 2-3% of all genes in the genome. The function of most miRNAs is largely unknown, but many miRNAs in invertebrates and vertebrates are clearly involved in important cellular processes such as differentiation and development. It is estimated that up to one third of all human genes may be miRNA targets.
The ability to control the rates of metabolic processes in response to changes in the internal or external environment is indispensable for all living cells. Mechanisms that are essential for metabolic control and maintenance of homeostasis are complex and involve transcriptional, translational, posttranslational and allosteric regulation. MiRNAs constitute a novel class of genes that add a new level of regulation and fine-tuning for gene expression that is likely to be important for a wide range of cellular functions, including metabolism.
We are studying the biological function of miRNAs in pancreatic islets, liver, intestine and muscle. We have developed technologies to systematically identify the miRNA target genes and to study the biological effects that result from overexpression of silencing of specific miRNAs. Overexpression and silencing of specific miRNAs in vivo will allow us to identify their targets and study the resulting phenotypes. The elucidation of environmental or genetic factors that affect miRNA expression, identification of miRNA targets and analysis of signaling pathways that affect miRNA function will be essential for a comprehensive understanding of these regulatory RNAs in normal and disease states. Once this information is available a rational approach can be taken to design novel therapeutic strategies that aim to correct inherited and acquired diseases.
HDL particles are thought to protect against atherosclerosis primarily by mediating the return of excess tissue cholesterol to the liver for excretion in bile. Mature HDL particles are generated from lipid-free apoA-I or lipid-poor preβ-HDL that are considered the initial extracellular acceptor of cellular cholesterol upon efflux from peripheral tissues. These precursors are either produced as nascent HDL by the liver or are released from lipolysed VLDL and chylomicrons. Cellular cholesterol taken up by preβ-HDL is subsequently esterified by the action of lethitin-cholesterol acyltransferase (LCAT), which leads to maturation and increased particle size. Esterified cholesterol from mature HDL particles can be taken up by the liver directly by whole particle or selective uptake or indirectly via exchange of triglycerides and cholesterol esters into low density lipoproteins (LDLs). This indirect pathway involves cholesterol ester transfer protein (CETP), a gene that is absent in mice. We have discovered that mice lacking apolipoprotein M (apoM) have markedly reduced plasma HDL levels, large HDL particles, lack preβ-HDL and exhibit increased susceptibility to develop atherosclerotic lesions. ApoM is a 26 kD apolipoprotein, an evolutionarily conserved gene and distinct member of the lipocalin family that is expressed in the liver and kidney and in plasma is associated with HDL particles. Current areas of investigation include the role of apoM in preβ-HDL formation, HDL metabolism and reverse cholesterol transport.
In collaboration with scientists at the Rockefeller University (New York) and the Broad Institute (Cambridge, U.S.) we are performing comprehensive genetic analysis in the Micronesian population of Kosrae (a founder population through introduction of two genetic bottlenecks) in an attempt to identify susceptibility genes responsible for obesity, diabetes, dyslipoproteinemias and hypertension. Ongoing studies include a comprehensive SNP genotyping effort of 3200 subjects with >600,000 SNPs. Future work will involve the evaluation of genetic variations in genes associated with type 2 diabetes.
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