Grants and Contracts Details
Elevation of ApoB-containing lipoproteins is a key risk factor for the development of atherosclerosis. Heparin binding EGF-like growth factor (HB-EGF) is an EGFR ligand that mediates EGFR transactivation. Circulatory HB-EGF level is correlated with cholesterol level in the blood stream and with risk of coronary artery disease in human. We demonstrated that the HB-EGF targeting using ASO administration in hyperlipidemic mouse models showed a remarkable lipid-lowering and effective protection against atherosclerosis. Mechanistically, the HB-EGF targeting significantly suppressed hepatic VLDL secretion without changing heparin-releasable plasma TG hydrolytic activity. Recombinant HB-EGF injection enhanced the secretion by agonistic effects. From these preliminary results, we hypothesize that the hepatic HB-EGF signaling is a novel key positive regulator for the hepatic VLDL assembly/secretion. With three specific aims, we will test the hypothesis with focus on deciphering of regulatory mechanism of hepatic VLDL secretion by HB-EGF signaling. Specific aim 1 is to examine the effects of liver-specific HB-EGF knockdown on the hepatic VLDL secretion and induction of hyperlipidemia and atherosclerosis in a mouse model. HB-EGF-floxed mice in C57BL/6 genetic background are available in PI lab. We will inject liver-Cre expressing adeno-associated virus (AAV) to induce liver-specific HB-EGF knockout in the mice. In these mice, we will measure the HB-EGF knockdown effects on hepatic VLDL secretion rate and development of hyperlipidemia and atherosclerosis. For the later, the floxed mice will be crossed with LDLR KO mice under the same genetic background. Specific aim 2 is to identify intracellular signaling pathway of HB-EGF for the regulation of hepatic VLDL production in hepatocytes. Using primary culture of mouse hepatocytes, we will identify HB-EGF signaling pathways leading to VLDL production. Technically, we radiolabel and measure secretions of freshly synthesized TG and apoB as surrogates for VLDL particle. Specific aim 3 is to determine the role of HB-EGF signaling on the lipid substrate accessibility, apoB stability, and MTP functions, which are key factors determining hepatic VLDL production rate. Technically, we will use primary hepatocytes from the mice pretreated with control and HB-EGF ASO to study the HB-EGF knockdown effects on the above three factors for VLDL secretion. In conclusion, in this study, we demonstrate that the HB-EGF signaling is a key regulator for the hepatic VLDL production and suggest a potential of the HB-EGF targeting to treat hyperlipidemia.
|Effective start/end date||7/1/17 → 6/30/19|
- American Heart Association: $77,000.00
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