Biochemistry, Lipoprotein Lipase


Article Author:
Yasaman Pirahanchi


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Sandeep Sharma


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Updated:
1/20/2019 8:09:23 AM

Introduction

Lipoprotein lipase (LPL) is an extracellular enzyme on the vascular endothelial surface that degrades circulating triglycerides in the bloodstream. These triglycerides are embedded in very low-density lipoproteins (VLDL) and in chylomicrons that travel through the bloodstream. The role of lipoprotein lipase is significant in understanding the pathophysiology of type one familial dyslipidemias, or hyperchylomicronemia, and its clinical manifestations. LPL also plays a significant role in understanding the cardiac pharmacology of fibrates as a class of medications and in the management of patients with high levels of serum triglycerides. In this review, we will explore the function, pathophysiology, and clinical relevance of lipoprotein lipase.[1]

Molecular

The structure of lipoprotein lipase remains undetermined. But it is similar to the enzymes in lipase family and is composed of two distinct regions. The N-terminal domain has a lipolytic active site and C- terminal domain. These two regions attach using a peptide link.

Function

Lipoprotein lipase is an enzyme that degrades circulating triglycerides in the bloodstream. These triglycerides are embedded in very low-density lipoproteins (VLDL) and in chylomicrons that travel through the bloodstream. Lipoprotein lipase is an extracellular enzyme and is found on the vascular endothelial surface, anchored to capillary walls. It is predominantly in adipose tissue, muscle, and heart tissue but it is not present 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 for 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, and the fatty acids are transferred to adipocytes and skeletal muscle, while the chylomicron remnants are taken up by the liver 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 that the plasma of these patients has a milky appearance. There is also significantly increased levels of chylomicrons in the blood of these individuals.[2]

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 normally removes triglycerides from chylomicrons, and if this process does not function, initial triglyceride breakdown cannot take place. 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.[3]

Patients with hyperchylomicronemia present with recurrent pancreatitis, enlarged liver, and xanthomas because of lack of triglyceride removal from chylomicrons and consequent increased levels of serum triglycerides and increased chylomicrons. This buildup eventually leads to triglyceride accumulation in the pancreas, in the liver, and deposit 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. Elevated triglycerides can cause acute pancreatitis; this may involve increased chylomicrons in the plasma. 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 then break down these triglycerides, leading to the release of triglyceride breakdown products including free fatty acids. This increase in free fatty acids can injure the tissue of the pancreas leading to pancreatitis.[4]

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 do not have any clear increased risk for atherosclerosis. Orlistat is a medication that can also be used to improve hyperchylomicronemia by decreasing the risk of pancreatitis; it is a pancreatic lipase inhibitor given before meals.[5]

Clinical Significance

Lipoprotein is clinically significant in cardiac pharmacology, specifically in cholesterol management. Fibrates, such as fenofibrate, bezafibrate, and gemfibrozil, which 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 decreased serum triglyceride levels, as they increase hydrolysis of VLDL and chylomicron triglycerides via lipoprotein lipase. Thus, fibrates are indicated for patients with extremely elevated levels of triglycerides. Fibrates decrease serum LDL mildly by reducing VLDL; however, statins are the first line therapy for lowering LDL.  Fibrates also induce high-density lipoprotein (HDL) synthesis, increasing serum HDL mildly by activating apolipoprotein A1 and apolipoprotein A2 which will create 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).[6]

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. Free fatty acids are formed by LPL and macrophages then re-esterify them, which leads to the accumulation of 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.[7]


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Biochemistry, Lipoprotein Lipase - Questions

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Activation of vascular bound lipoprotein lipase is performed by which of the following apoproteins?



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The hydrolysis of chylomicron triglyceride occurs by action of which of the following?



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A mouse model was designed with a deletion in the peroxisome proliferator-activated receptor alpha. How would this impact the activity of lipoprotein lipase and why?



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A 15-year-old male presents with a history of recurrent pancreatitis, enlarged liver, and multiple xanthomas. Serum triglycerides are at 300 mg/dL. Serum levels of which of the following would also be expected to be elevated?



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A 16-year-old female presents with a history of recurrent pancreatitis. Upon physical exam, multiple xanthomas were found, and hepatomegaly was observed. Labs indicated elevated levels of triglycerides. What is the enzyme dysfunction in this disease?



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Biochemistry, Lipoprotein Lipase - References

References

Kobayashi J,Mabuchi H, Lipoprotein lipase and atherosclerosis. Annals of clinical biochemistry. 2015 Nov;     [PubMed]
Mead JR,Irvine SA,Ramji DP, Lipoprotein lipase: structure, function, regulation, and role in disease. Journal of molecular medicine (Berlin, Germany). 2002 Dec;     [PubMed]
Falko JM, Familial Chylomicronemia Syndrome: A Clinical Guide For Endocrinologists. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2018 Aug;     [PubMed]
Blackett P,Tryggestad J,Krishnan S,Li S,Xu W,Alaupovic P,Quiroga C,Copeland K, Lipoprotein abnormalities in compound heterozygous lipoprotein lipase deficiency after treatment with a low-fat diet and orlistat. Journal of clinical lipidology. 2013 Mar-Apr;     [PubMed]
Blom DJ,O'Dea L,Digenio A,Alexander VJ,Karwatowska-Prokopczuk E,Williams KR,Hemphill L,Muñiz-Grijalvo O,Santos RD,Baum S,Witztum JL, Characterizing familial chylomicronemia syndrome: Baseline data of the APPROACH study. Journal of clinical lipidology. 2018 Sep - Oct;     [PubMed]
Yuan G,Al-Shali KZ,Hegele RA, Hypertriglyceridemia: its etiology, effects and treatment. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 2007 Apr 10;     [PubMed]
Okopień B,Bułdak Ł,Bołdys A, Benefits and risks of the treatment with fibrates--a comprehensive summary. Expert review of clinical pharmacology. 2018 Nov;     [PubMed]

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