Biochemistry, Lipoprotein Lipase

Molecular Level

The structure of lipoprotein lipase is similar to the enzymes in the lipase family and comprises two distinct regions. LPL has an N-terminal domain with a lipolytic active site and a C-terminal domain. These two regions attach using a peptide link. Recent x-ray crystallography and biochemical experiments have provided more structural evidence revealing that lipoprotein lipase can be active as a monomer.[2][3] Also, Cryo-EM studies have shown that the inactive form of lipoprotein lipase is a polymer.[4]

Function

Lipoprotein lipase is an enzyme that degrades circulating triglycerides in the bloodstream. These triglycerides are embedded in very low-density lipoproteins (VLDL) and chylomicrons traveling through the bloodstream. Lipoprotein lipase is an extracellular enzyme on the vascular endothelial surface, anchored to capillary walls. This enzyme is predominantly in adipose tissue, muscle, and heart tissue but not in the liver, as the liver has hepatic lipase. Lipoprotein functions to convert triglycerides to fatty acids and glycerol.

Fatty acids liberated from the triglycerides are then used for storage in adipose tissue or fuel in skeletal or cardiac muscle. Lipoprotein lipase requires apolipoprotein-CII, a cofactor for lipoprotein lipase, which is carried by a chylomicron as well as by very low-density lipoprotein and intermediate-density lipoproteins (IDL), for activation. Lipoprotein lipase will shrink the chylomicrons by removing the fatty acids from triglycerides, which are transferred to adipocytes and skeletal muscle. At the same time, the liver takes up the chylomicron remnants via receptor-mediated endocytosis.[1]

Pathophysiology

The pathophysiology of lipoprotein lipase is evident in familial dyslipidemias (specifically type one) or hyperchylomicronemia. Hyperchylomicronemia is an autosomal recessive genetically inherited disease in which there is a significant increase in levels of triglycerides, >1000, such that the plasma of these patients has a milky appearance. There are also significantly increased chylomicron levels in these individuals' blood.[5]

In both type one familial dyslipidemia or hyperchylomicronemia, there is severe LPL dysfunction; this is because of LPL deficiency and LPL co-factor deficiency, or apolipoprotein C2 deficiency, which is necessary for activation of lipoprotein lipase. LPL typically removes triglycerides from chylomicrons; if this process does not function, initial triglyceride breakdown cannot occur. Therefore, triglycerides will build up in the serum, and chylomicrons will grow very large as they are full of triglycerides, which are not undergoing removal.[6]

Patients with hyperchylomicronemia present with recurrent pancreatitis, enlarged liver, and xanthomas because of a lack of triglyceride removal from chylomicrons and increased serum triglycerides and chylomicrons levels. This buildup eventually leads to triglyceride accumulation in the pancreas, in the liver, and deposits on the skin, causing these clinical manifestations. Xanthomas occur because of plaques of lipid-laden histiocytes, as macrophages in the bloodstream endocytose excess serum triglycerides. Clinically, xanthomas appear as skin bumps or along the eyelids of patients with high serum lipid levels.[7]

Elevated triglycerides can cause acute pancreatitis, which may involve increased plasma chylomicrons. These chylomicrons can obstruct capillaries, and this may cause decreased blood flow and, ultimately, ischemia. When vessel damage occurs, this can cause pancreatic lipases to have access to serum triglycerides. Pancreatic lipases may break down these triglycerides, releasing triglyceride breakdown products, including free fatty acids. This increase in free fatty acids can injure the tissue of the pancreas leading to pancreatitis.[7]

Treatment for type 1 familial dyslipidemia or hyperchylomicronemia is a very low-fat diet. With careful monitoring of diet, patients often have normal lifespans. Additionally, with tight dietary lipid control, patients have no apparent increased risk for atherosclerosis. Orlistat is a medication that can also improve hyperchylomicronemia by decreasing the risk of pancreatitis; it is a pancreatic lipase inhibitor given before meals.[8]

Clinical Significance

Lipoprotein is clinically significant in cardiac pharmacology, specifically in cholesterol management. Fibrates, such as fenofibrate, bezafibrate, and gemfibrozil, work by activating peroxisome proliferator-activated receptor alpha (PPAR-alpha) and upregulating lipoprotein lipase. Activation of PPAR alpha leads to gene transcription modification. Modified gene transcription leads to increased lipoprotein lipase activity. PPAR-alpha activity also increases the oxidation of fatty acids in the liver, which leads to decreased levels of very low-density lipoprotein. Ultimately, this leads to reduced serum triglyceride levels, as they increase hydrolysis of VLDL and chylomicron triglycerides via lipoprotein lipase. Thus, fibrates are indicated for patients with highly elevated levels of triglycerides.

Fibrates decrease serum LDL mildly by reducing VLDL; however, statins are the first-line therapy for lowering LDL. Fibrates induce high-density lipoprotein (HDL) synthesis, mildly increasing serum HDL by activating apolipoprotein A1 and apolipoprotein A2, creating nascent HDLs. Clinically, fibrates are primarily indicated for decreasing blood triglyceride levels, and they are the most effective class of drugs for this function. Side effects of fibrates include cholesterol gallstones, as they increase the cholesterol content of bile.

Fibrates may also cause rhabdomyolysis, and the risk of myopathy is higher when combined with statins. Fibrates can also cause increased levels of liver enzymes such as alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase (GGT). Fibrates are usually combined with other cholesterol-lowering treatments as they increase low-density lipoproteins (LDL).[9]

Clinically, LPL plays a significant role in the progression of atherosclerosis. LPL is a component in atherosclerotic lesions, which derive from macrophages. Furthermore, patients with advanced atherosclerosis were found to have elevated LPL mass and activity in their post-heparin plasma. LPL contributes to atherogenic lipoprotein formation. LPL acts on chylomicrons and VLDL to hydrolyze triglycerides from them and form VLDL remnants and chylomicron remnants. VLDL remnants and chylomicron remnants are composed of a high concentration of cholesterol esters and then get incorporated into macrophages. LPL creates free fatty acids, and macrophages then re-esterify them, accumulating cholesterol esters in macrophages, causing macrophages to transform into foam cells. LPL catalyzed the conversion of VLDL to Intermediate density lipoproteins (IDL), which hepatic lipases then convert to low-density lipoprotein (LDL). Foam cells also form when macrophages incorporate oxidized LDL via their scavenger receptor in the vascular endothelium.[10]