Regulating intestinal function to reduce atherogenic lipoproteins

Abstract

Significant knowledge regarding different molecules involved in the transport of dietary fat into the circulation has been garnered. Studies point to the possibility that accumulation of intestine-derived lipoproteins in the plasma could contribute to atherosclerosis. This article provides a brief overview of dietary lipid metabolism and studies in mice supporting the hypothesis that intestinal lipoproteins contribute to atherosclerosis. Deficiencies in lipoprotein lipase and Gpihbp1, and overexpression of heparanse in mice, are associated with increases in atherosclerosis, suggesting that defects in catabolism of larger lipoproteins in the plasma contribute to atherosclerosis. Furthermore, inositol-requiring enzyme 1β-deficient mice that produce more intestinal lipoproteins also develop more atherosclerosis. Thus, increases in plasma intestinal lipoproteins due to either overproduction or reduced catabolism result in augmented atherosclerosis. Intestinal lipoproteins tend to adhere strongly to subendothelial proteoglycans, elicit an inflammatory response by endothelial cells and activate macrophages, contributing to the initiation and progression of the disease. Thus, molecules that reduce intestinal lipid absorption can be useful in lowering atherosclerosis.

Keywords: MTP; apoB; atherosclerosis; cholesterol; chylomicronemia; hyperlipidemia; hypertriglyceridemia; lipoproteins; triglyceride.

Figure 1. Absorption of dietary fat

Dietary fat is emulsified by bile acids in the gut lumen. The emulsified lipids are hydrolyzed by pancreatic lipases. FFAs and MAGs are taken up by enterocytes and used for the synthesis of TAGs in the ER membrane by different enzymes involving two different pathways (Figure 2). Similarly, FC arising from the hydrolysis of CEs enters the enterocytes. NPC1L1 plays a critical role in the uptake of FC by enterocytes. On the other hand, ABCG5 and ABCG8 regulate the efflux of cholesterol from enterocytes into the intestinal lumen. Within the enterocytes, FC is delivered to the ER where it is converted to CEs by ACAT1 and ACAT2 enzymes. The formation of chylomicrons begins using apoB48 as a scaffold, with the help of a chaperone, MTP. Chylomicrons are transported from the ER to the Golgi apparatus via prechylomicron transport vesicles, where they undergo further modifications involving addition of lipids and apolipoproteins. The mature chylomicrons are released by the enterocytes from the basolateral side and enter the lymphatic circulation. ACAT: Acyl-coenzyme A:cholesterol acyltransferase; CE: Cholesterol ester; DGAT: Diacylglycerol acyltransferase; ER: Endoplasmic reticulum; FC: Free cholesterol; FFA: Free fatty acid; MAG: Monoacylglycerol; MGAT: Monoacylglycerol acyltransferase; TAG: Triglyceride.

Figure 2. Triglyceride synthesis in enterocytes

Two different pathways are involved in the synthesis of TAGs: the MAG pathway and G-3-P pathways. MAG is the predominant pathway in enterocytes that is involved in TAG synthesis. The G-3-P pathway is the major pathway for TAG synthesis by the liver. Dashed arrow used to denote a pathway not relevant to this article. DAG: Diacylglycerol; DGAT: Diacylglycerol acyltransferase; G-3-P: Glycerol-3-phosphate; GPAT: Glycerol-3-phosphate acyltransferanse; LPA: Lysophosphatidic acid; LPAAT: Lysophosphatidic acid acyltransferase; MAG: Monoacylglyerol; MGAT: Monoacylglycerol acyltransferase; PA: Phosphatidic acid; PAP: Phosphatidic acid phosphatase; PC: Phosphatidylcholine; PE: Phosphatidylethanolamine; TAG: Triglyceride.

Figure 3. Hydrolysis of chylomicron lipids by lipoprotein lipase

As described in Figure 1, CMs are secreted towards the basolateral side by enterocytes. These particles are then transported via the lymphatic system to the circulation at the thoracic duct. In the circulation, these particles acquire apoCII that interacts with lipoprotein lipase attached to a transmembrane protein, Gpihbp1, anchored in the endothelial cell membranes. This brings CMs to lipoprotein lipase. Furthermore, it activates the enzyme to initiate hydrolysis of TAGs present in CMs. FFAs generated by this hydrolysis are taken up by the endothelial cells. After hydrolysis, remnant lipoproteins are released from the endothelial cell surface. These particles acquire apoE from plasma and are mainly cleared by the liver. CE: Cholesterol ester; CM: Chylomicron; FFA: Free fatty acid; TAG: Triglyceride.