Fellowship for Olivia Hage: The role of Dennd5b in Triglyceride-Rich Lipoprotein Secretion from the Liver and Intestine

ABSTRACT Triacylglycerides (TAGs) compromise the majority of lipid in a common human diet. Not only does TAG metabolism vary widely on a person-to-person basis, but its’ dysregulation leads to a plethora of diseases and metabolic phenotypes. Hypertriglyceridemia is a diagnostic feature of metabolic syndrome and is positively correlated with risk of cardiovascular disease1, and insulin resistance2 Lower post-prandial plasma TAG has been linked to lower rates of ischemic events and deaths from atherosclerotic cardiovascular disease. Physiologic regulation of TAG largely functions through two organs: dietary absorption via the small intestine and endogenous production by the liver. In intestinal and hepatic tissues, TAGs are packaged into analogous vesicles for transport from the Golgi to the plasma membrane (PM): enterocyte chylomicron- secretory vesicles (CSVs)3 and hepatocyte Post-TGN (Trans Golgi Network) VLDL Transport Vesicles (PG-VTVs)4. Current literature lacks mechanistic understanding of the molecular machinery that coordinates the movement, vesicle-PM fusion, and secretion of TLRs (Triglyceride-Rich Lipoproteins) into circulation34. A more detailed understanding of this process would provide insight into the pathophysiology of both fasting and post-prandial hypertriglyceridemia and the relationship between TRLs and cardiovascular risk. Our lab previously reported that Dennd5b-deficient mice are resistant to diet-induced obesity and hepatic steatosis. Our preliminary data demonstrate that after ingestion of lipid, Dennd5b-/- murine enterocytes accumulate CSVs3 and DENND5B-/- human hepatocytes fail to secrete TAG while maintaining normal intracellular TAG concentrations. These data support a role for the protein Dennd5b in trafficking post-Golgi TLR-containing vesicles in both the gut and liver. However, the cellular functions of Dennd5b behind its role in these processes is unknown. Furthermore, there is a knowledge gap in the existing literature and our understanding of how such large TRL cargo are secreted from these tissues. The current proposal will examine the intracellular localization of Dennd5b protein in liver and small intestinal tissues and will identify DENND5B-interacting proteins that likely participate in the process of TRL secretion.