Triglyceride synthesis and very low-density lipoprotein (VLDL) secretion machinery

The triglyceride synthesis and very low-density lipoprotein (VLDL) secretion machinery is a coordinated hepatic pathway responsible for the production of triglycerides and their assembly into VLDL particles for systemic lipid transport. This process involves key enzymes such as diacylglycerol O-acyltransferase (DGAT), which performs the final step of triglyceride synthesis, and the microsomal triglyceride transfer protein (MTP), which facilitates the loading of lipids onto apolipoprotein B-100 (ApoB-100) [1][2]. Once assembled, VLDL particles are secreted into the blood, where they deliver fatty acids to peripheral tissues. Dysregulation of this machinery, often characterized by VLDL overproduction, is a central driver of hypertriglyceridemia and is closely linked to metabolic syndrome, type 2 diabetes, and atherosclerotic cardiovascular disease [3][4]. Pharmacological targeting of this machinery, through MTP inhibitors like lomitapide or ApoB-targeted antisense oligonucleotides like mipomersen, provides a potent means of lowering circulating lipids, particularly in severe genetic dyslipidemias [5][6]. However, these interventions carry significant risks, most notably the accumulation of lipids within the liver (hepatic steatosis) due to the blockage of lipid export [5]. Citations: [1] Hussain MM, et al. (2003). J Lipid Res. 44(4):635-49. [2] Yen CL, et al. (2008). J Lipid Res. 49(11):2283-301. [3] Adiels M, et al. (2008). J Clin Invest. 118(3):788-94. [4] Borén J, et al. (2022). Eur Heart J. 43(8):725-759. [5] Cuchel M, et al. (2013). Lancet. 381(9860):40-46. [6] Thomas GS, et al. (2013). Expert Opin Orphan Drugs. 1(1):77-88.

Other names

Hepatic VLDL assembly pathwayTriglyceride-rich lipoprotein production machineryApoB-lipoprotein secretion pathwayVLDL secretion pathway

Inhibition of microsomal triglyceride transfer protein (MTP), antisense-mediated inhibition of apolipoprotein B-100 (ApoB-100) or apolipoprotein C-III (ApoC-III) mRNA, and inhibition of angiopoietin-like 3 (ANGPTL3) or diacylglycerol O-acyltransferase (DGAT).