Research
The Finck Lab is interested in two general areas of intermediary metabolism.
A primary focus over the past few years has been on mitochondrial metabolism of pyruvate as regulated by the mitochondrial pyruvate carrier complex. This work has also led us to focus on other facets of mitochondrial metabolism as well.
Another longstanding interest is in enzymes involved in the synthesis of triglycerides and other glycerolipids with particular focus on the [1] lipin family proteins and [2] monoacylglycerol acyltransferases.
The role of the mitochondrial pyruvate carrier (MPC) in health and disease
Pyruvate is a three-carbon intermediate that is synthesized in the cytosol as the end product of glycolysis, by the oxidation of lactate, and from a variety of amino acids. However, in order to undergo further metabolism by oxidation or carboxylation, pyruvate must cross the impermeable inner mitochondrial membrane to enter the mitochondrial matrix. The transport of pyruvate into the mitochondrion is mediated by the mitochondrial pyruvate carrier (MPC); a heterodimeric complex of two proteins MPC1 and MPC2.
Once in the mitochondrial matrix, pyruvate can be oxidized by pyruvate dehydrogenase (PDH) to generate acetyl-CoA, which many types of cells use to produce reducing equivalents (NADH) to drive ATP synthesis. Pyruvate can also be carboxylated by pyruvate carboxylase (PC) to form oxaloacetate (OAA) in an anaplerotic reaction. OAA can be condensed with acetyl-CoA to form citrate or converted to malate. These reactions are required and critical for a variety of biological and biosynthetic pathways including synthesis of glucose via gluconeogenesis, de novo lipogenesis, and synthesis of neurotransmitters and other lipids.
Work to date has demonstrated important roles for the MPC in regulating metabolism in liver, heart, and pancreatic beta cells. We are very interesting in the development and implementation of MPC inhibitors for treating diabetes, nonalcoholic fatty liver disease, and other metabolic diseases.
Regulation of glycerolipid synthesis and turnover
The capacity to synthesize and store triglycerides is a fundamental process that improves chances of survival in times of nutrient scarcity. However, excessive storage of fat, such as occurs in obesity, is associated with development of a variety of cardiometabolic diseases and has become a public health crisis in many countries. Proper regulation of lipid storage is critical for maintaining physiological homeostasis and the health of the organism.
To synthesize triglycerides and other complex glycerolipids, fatty acids are sequentially esterified to a glycerol backbone. There are two major pathways for triglyceride synthesis. The canonical pathway for fatty acid incorporation of triglyceride begins with glycerol-3-phosphate. Through sequential acylation of the glycerol backbone, an intermediate called phosphatidic acid (PA) is formed and then dephosphorylated by lipin proteins to form diacylglycerol (DAG). The other pathway of triglyceride synthesis involves the acylation of monoacylglycerol by monoacylglycerol acyltransferase (MGAT) enzymes to form DAG. These two pathways converge and in both cases, DAG acyltransferases add a fatty acyl moiety to create triglyceride. Our lab has been interested in the two enzymes that form DAG (lipins and MGATs) for several years. This work has demonstrated important roles for these proteins in regulating adiposity, controlling various signaling pathways that are regulated by PA and DAG, and as mediators of the pathogenesis of metabolic diseases such as insulin resistance, diabetes, and nonalcoholic fatty liver disease.
