Hepatic production of apo B-containing lipoproteins plays an integral role in lipid metabolism. Imbalances of the production of apo B-containing lipoproteins or their removal by the liver are associated with several diseases including atherosclerosis, obesity and diabetes. Data obtained using cultured hepatocytes and genetically altered mice have led us to hypothesize that hepatic secretion of apo B containing lipoproteins is regulated post-transcriptionally. During its translation, apo B has two metabolic fates: translocation into the lumen of the endoplasmic reticulum (ER) during the addition of lipid to form a lipoprotein particle or degradation by an ubiquitin-dependent proteasome pathway. Microsomal triglyceride transfer protein (MTP) and the supply of glycerolipids (phospholipids and triglycerides) play an essential role in mediating apo B translocation and assembly into a lipoprotein particle. Based on new and intriguing insights gained during the previous funding period, we will direct our efforts to the following Specific Aims:
Specific Aim 1 : To define how COUP-TFII interacts with a conserved DR1 site in the MTP promoter and alters gene transcription in rat hepatoma cells and in vivo in the livers of mice.
Specific Aim 2 : To examine the role of ubiquitin-dependent proteasome degradation in regulating the metabolic fate of apo B in vivo in the livers of mice.
Specific Aim 3 : To examine the mechanism through which genetic deletion of Txnip alters the flow of carbon units into lipids and secretion of apo B-containing lipoproteins. Clearly, MTP-mediated translocation and lipid transfer is an effective target for ameliorating one of the most severe forms of hypercholesterolemia (for which most other drugs [e.g. statins] are ineffective; i.e., homozygous familial hypercholesterolemia). We are confident that our proposed studies will provide new insights that will add further proof to the feasibility and advance the therapeutic potential of controlling the apo B processing pathway.
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