Lipoprotein Metabolism

A. Intestinal Lipoproteins and Transport of Dietary Lipids in Diabetes Mellitus

Chylomicrons are assembled in the enterocytes of the small intestine after ingestion of dietary fat (triglyceride) and cholesterol. In the lymph and the blood, chylomicrons acquire several apolipoproteins, including apo C-II, apo C-III, and apo E. In the capillary beds of adipose tissue and muscle, chylomicrons interact with the enzyme lipoprotein lipase (LPL), which is activated by apo C-II, and the chylomicron core triglyceride is hydrolyzed. The lipolytic products, free fatty acids, can be taken up by fat cells where they are converted back into triglyceride, or by muscle cells, where they can be used for energy. Apo C-III can inhibit lipolysis, and the balance of apo C-II and apo C-III determines, in part, the efficiency with which LPL hydrolyzes chylomicron triglyceride. The product of this lipolytic process is the chylomicron remnant, which has only about 25% of the original chylomicron triglyceride remaining. Importantly, the chylomicron remnants are relatively enriched in cholesteryl esters; they have not lost any of the dietary cholesterol first incorporated into the chylomicron in the enterocyte, and they have accumulated cholesteryl esters transferred from HDL in the circulation (see below). The cholesterol-rich chylomicron remnants are also enriched in apo E and interact with several receptor pathways on hepatocytes that rapidly remove them from the circulation. Uptake of chylomicron remnants involves binding to the LDL receptor, the LDL receptor-related protein (LRP), and cell-surface proteoglycans; apo E appears to play a crucial role in each of these processes.

In patients with diabetes, chylomicron and chylomicron-remnant metabolism can be altered significantly. Thus, in patients with poorly controlled type 1 DM, LPL, which is regulated at both the level of gene transcription and cellular processing by insulin, can be low, leading to inefficient lipolysis of the chylomi-cron triglyceride. As a result, postprandial triglyceride levels can be increased in poorly treated type 1 diabetics. Insulin therapy rapidly reverses this condition resulting in the clearance of chylomicron triglycerides from plasma. However, in well-controlled type 1 DM, LPL measured in postheparin plasma (heparin releases LPL from the surface of endothelial cells where it is usually found), as well as adipose tissue LPL can be normal or increased, and chylomicron triglyceride clearance can be normal.

Defective metabolism of chylomicrons has also been observed in type 2 DM, although LPL is normal or only slightly reduced in this group. Confounding £

a full understanding of postprandial lipemia in patients with type 2 DM is the g underlying insulin resistance and the associated dyslipidemia. Since fasting hy- <j pertriglyceridemia is characteristic of patients with type 2 DM, and is correlated with increased postprandial triglyceride levels, it is difficult to identify a direct effect of type 2 DM on chylomicron metabolism. For example, chylomicrons a

& u and VLDL compete for the same supply of LPL. If LPL is limited or VLDL secretion from the liver is very high, lipolysis of chylomicron triglyceride is likely to be impaired.

Once the chylomicron has undergone adequate lipolysis, it becomes the chylomicron remnant. As noted above, apo E is thought to play a critical role in the hepatic uptake of chylomicron remnants, and some studies have indicated a role for the apo E2 phenotype in the hyperlipidemia of diabetes. Apo E2 is an allelic form of apo E that is found in about 10% of the population and is defective in binding to the LDL receptor. If a patient with DM has an apo E allele, this might impact negatively on the removal of chylomicron remnants in those patients. On the other hand, apo E2 appears to interact normally with LRP, the alternative receptor for remnants. Another possible reason for decreased remnant removal could be that apo E becomes glycated and that this modification of apo E causes a loss of affinity for either the LDL or the LRP receptors. Finally, hepatic triglyceride lipase (HTGL), which both hydrolyzes chylomicron- and VLDL-remnant triglycerides as well as acting as a bridge for those molecules to bind to the liver cell surface, might be reduced in patients with DM. However, several studies have indicated that HTGL is elevated in hypertriglyceridemic individuals with or without DM.

In summary, several studies have demonstrated increased postprandial li-pemia in patients with DM. In untreated type 1 patients, reduced LPL is probably the key component of the problem and the lipemia can be reduced by good gly-cemic control. In patients with type 2 DM, the underlying fasting dyslipidemia is likely to be the major contributor to the postprandial lipemia, with LPL playing a minor role. Accumulation of atherogenic postprandial remnants is also commonly observed in patients with DM, but the basis for this abnormality is less well understood. Finally, the postprandial lipemia commonly present in type 2 DM may be an important contributor to low HDL cholesterol levels characteristic of patients with this disease (Table 3).

Table 3 Abnormalities in Postprandial Lipid Metabolism

Type of diabetes

Poorly controlled

Well controlled

Type 1

Decreased LPL

Normal or increased LPL

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