Heart disease is the leading cause of mortality worldwide. One significant risk factor for developing heart disease is uncontrolled high circulating triglycerides. The enzyme Lipoprotein Lipase (LPL) hydrolyzes triglycerides packaged in circulating lipoprotein particles. For this reason, LPL activity and levels are closely correlated with the risk of developing cardiovascular disease. Understanding LPL regulation is important for understanding the role of LPL in disease. The transcriptional regulation of the LPL gene has been well characterized. LPL is synthesized in the parenchyma of tissues including adipose and muscle and its transcription is tightly regulated. Post-translationally, LPL is thought to be stored in secretory vesicles and released by unidentified physiological cues. LPL from intracellular stores is actively degraded in lysosomes. It is not clear how this LPL is targeted for degradation as opposed to secretion. One clue to this regulation comes from Type 2 Diabetes (T2D). Insulin signaling is essential for normal LPL activity and patients with insulin resistance experience reduced LPL activity. We hypothesize that insulin influences LPL stability to regulate its trafficking. The objective of this proposal is to understand the molecular mechanisms of LPL trafficking in adipocytes.
In aim 1, we will examine the intracellular trafficking and degradation of LPL in adipose tissue.
In aim 2 we will describe the role of Tankyrase 1 in LPL trafficking. We will accomplish these aims using Western blotting, fixed-cell, cell fractionation and live-cell microscopy. These studies extend the fundamental molecular mechanisms of LPL regulation and identify new targets for treating LPL deficiency during T2D.
Understanding how type 2 diabetes contributes to high blood triglycerides and cardiovascular disease (CVD) is important for the treatment each disease. This project examines the role of insulin signaling in the regulation of Lipoprotein Lipase, an enzyme essential for the clearance of triglycerides from the blood. The project aims to identify insulin-regulated steps in LPL trafficking, and thus potential steps for treating CVD in type 2 diabetes.