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Lipoproteins and Select Associated Health Issues

Written by: Elizabeth M. • 2017 Scholar


Introduction

Cholesterol and triacylglycerol are important for cell membrane structure and function.  They are delivered to cells in a series of different forms and through different pathways.  Because they are hydrophobic and their environment is mostly hydrophilic (blood and lymph), they are transported using proteins in vesicles called lipoproteins.  Diet, hormones, and enzyme concentration all have an impact as to which lipoproteins are highest in blood plasma.  An imbalance of certain types of lipoproteins and their enzymes can lead to diseases like atherosclerosis, hepatic lipidosis or lipoprotein deficiency.

Lipids—Cholesterol and Triacylglycerol:

Cholesterol is a water-insoluble molecule, making it important for supporting animal membrane structure. It also is a precursor of many important biomolecules like steroid hormones, bile salts, and vitamin D (Mahley RW et al, 2006).   Animals get cholesterol both through their diet and cholesterol synthesis within their livers (Case LP et al, 2011).

Triacylglycerol is an ester made from three fatty acids connected to a glycerol backbone.  It is the body’s form of storing energy and is the main constituent of body fat.  Like cholesterol, it too is water-insoluble (Case LP et al, 2011).

Transporting Lipids

Due to their hydrophobic nature, it would be perhaps impossible for cholesterol, triacylglycerol, and fat-soluble vitamins to dissolve and be transported in the bloodstream, interstitium, or lymphatics unassisted.  The body adapted to this issue by packaging these lipids into hydrophilic transport particles called lipoproteins.  Lipoproteins are non-covalent spherical lipid and protein complexes.  The inner core contains the hydrophobic lipids.  The outer surface consists of a layer of hydrophilic non-esterified cholesterol, phospholipids, and proteins (receptor ligands called apolipoproteins).  There are different classifications of lipoproteins depending on their apolipoproteins, size, density, location, and function (Berg JM et al, 2002).

Chylomicrons—
The lipoprotein assembled within the intestinal mucosal cell is called a chylomicron.  Its job is to move lipids obtained from the diet into the lymphatic system then into the bloodstream to reach peripheral tissues.  The main apolipoprotein on the surface of a chylomicron is apolipoprotein B-48. Chylomicrons are the largest lipoprotein being 180 to 500 nm in diameter. They are also the least dense lipoprotein with its primary contents being triacylglycerol (Berg JM et al, 2002).

VLDL—
Produced in the liver, very low density lipoproteins (VLDLs) also transport triacylglycerol for peripheral tissue energy use or storage in adipose tissue.  In this regards they are similar to chylomicrons.  However, they are transporting endogenously produced triacylglycerol from the liver, not fat obtained from the diet.  VLDLs are the second largest lipoprotein whose major apoproteins are apolipoprotein B-100 and apolipoprotein E (Berg JM et al, 2002).  The apolipoprotein E receptor has a strong affinity for the enzyme, lipoprotein lipase (LPL) (Brown MS & Goldstein JL, 1986).

IDL—
Intermediate density lipoprotein (IDL) is a remnant lipoprotein of VLDL formed when some triacylglycerol have been removed.  It is believed to be strongly atherogenic. (Kim JY et al, 2011).  They are 25 to 35 nm in diameter and have multiple copies of apolipoprotein-E and one copy of apolipoprotein B-100. The remaining presence of apolipoprotein E make them an IDL as opposed to a low density lipoprotein (LDL) (Brown MS & Goldstein JL, 1986).   IDLs will either be recycled back to the liver or further processed into LDLs (Berg JM et al, 2002).

LDL—
LDL’s main function is to transport cholesterol in the blood to peripheral tissues. They lack apolipoprotein E and have a single apolipoprotein B-100 (Berg JM et al, 2002).  The predominate lipids in LDLs are in the form of cholesteryl esters and the polyunsaturated fatty acid, linoleate acid (Shelness GS & Sellers JA, 2000).  LDLs are formed from the removal of triacylglycerol from chylomicrons and VLDL mediated by the enzyme LPL.  LDL supply cholesterol to cells by binding to LDL receptors on endothelial or tissue cells (Berg JM et al, 2002).

HDL—
High density lipoproteins (HDLs) have the highest contents of protein and are therefore the most dense.  Like the LDLs, HDLs transport cholesterol; however, they move the cholesterol in the opposite direction.  Empty HDL secreted from the liver go to peripheral tissues and collect excess cholesterol from the tissue (Berg JM et al, 2002).  The cholesterol is taken back to the liver to be excreted directly into bile, or converted into bile acids and steroid hormones (Mahley RW et al, 2006). HDL is the predominant cholesterol carrier in dogs and cats (Christopher MM, 1997). 

LPL—
LPL is important in lipoprotein metabolism.  It is a water-soluble enzyme produced by adipocytes for fat storage, or produced by myocytes, islets, and macrophages for energy use (Wang H & Eckel RH, 2008). It unloads triacylglycerol from plasma chylomicrons and VLDLs, providing adjacent cells with fatty acids and glycerol.  (Tsutsumi K, 2003). The breakdown of chylomicrons result in chylomicron remnants, and the breakdown of VLDL result in IDL and the further hydrolyzed lipoprotein, LDL (Brown MS & Goldstein JL, 1986).

Selected Diseases Associated with Lipoproteins:

Atherosclerosis—
Often LDL is associated with “bad cholesterol” and HDL with “good cholesterol.” This is because excess LDL releases excess cholesterol to the macrophages within the endothelial lining.  This can cause inflammation and cholesterol build up, leading to a narrowing of the vessel.  The disease where there is a hardening and narrowing of the artery due to excess cholesterol deposits is called atherosclerosis (Wang L, 2009).

According to some studies, IDL and their associated remnant cholesterol were better predictors of the extent of atherosclerosis than LDL or VLDL (Nordestgaard BG & Tybjaerg-Hansen A,1992). Comparing IDL remnant cholesterol to LDL cholesterol, remnant cholesterol had double the association with ischemic heart disease (Varbo A et al, 2013).  High IDL also induced endothelial dysfunction through oxidative stress, was associated with chronic inflammation, and correlated to increased plasma triacylglycerol levels (Chapman MJ et al, 2011).  An increase in plasma triacylglycerol and decrease in HDL cholesterol are also indicators for an increased risk of coronary heart disease (Tsutsumi K, 2003).

Multiple studies have been conducted analyzing LPL activity and its correlation to coronary health. LPL has been shown to either have pro-atherogenic or anti-atherogenic properties depending on its location (Clee SM et al, 2000). LPL activity expressed by macrophages on the vessel wall is pro-atherogenic (Clee SM et al, 2000).  This could be due to the increased associated of LDL with the endothelial cell, or from vascular inflammation induced by FFAs and lipolysis (Wang L et al, 2009).  Increased LPL activity selectively within the plasma and non-endothelial tissue is considered anti-atherogenic.  It has been found to decrease plasma triacylglycerol and total cholesterol, both of which are associated with atherosclerosis (Clee SM et al, 2000). Dogs and cats are much more resistant to atherosclerosis compared to humans due to their relatively high HDL and low LDL concentrations (Christopher MM, 1997).

Hepatic Lipidosis—
Hepatic lipidosis is associated with overt liver dysfunction, common in fat cats that are starving (Dimski DS, 1997).  The pathophysiologic mechanisms of feline hepatic lipidosis remains elusive, but it can be characterized as more fats are going into the liver verses leaving it (Valtolina C & Favier RP, 2017).   In a normal cat or mammal, lipid levels rise within the liver due to HDL bringing fatty acids from fat stores and concurrent de novo lipogenesis.  Lipid levels decrease in the liver via VLDLs and fatty acids undergoing hepatic beta-oxidation (Valtolina C & Favier RP, 2017).  In starving cats, excess lipid is mobilized to the liver and the removal of hepatic lipid is compromised.  The diminished hepatic lipid removal could be due to protein malnutrition, carnitine deficiency, or oxidative damage to peroxisomes and other hepatic organelles. The cat may present with weight loss, depression, vomiting, icterus, and abnormal liver values (Dimski DS, 1997).

Lipoprotein Lipase Deficiency—
Individuals with LPL deficiency build up large amounts of chylomicrons and VLDLs in the plasma (Nordestgaard BG & Tybjaerg-Hansen A, 1992).  Though more specifically called hyperlipoproteinemia, this condition is often referred to as hyperlipidemia or hyperchylomicronemia (Case LP et al, 2011).  Hypertriglyceridemia from impaired triacylglycerol plasma clearance also develops (Ginzinger DG, 1999). 

Cats with LPL deficiency have a naturally occurring autosomal recessive Gly412Arg LPL gene mutation (Ginzinger DG et al,1996).  Depending on the individual’s rate of de novo synthesis of fat, cats homozygous for the deficiency have been found to either have normal to subnormal stores of body fat (Veltri BC et al, 2006;  Backus RC et al, 2001).  They also tend to have reduced body mass and growth (Ginzinger DG et al,1996).  Other physical signs of this condition may or may not be present (Case LP et al, 2011). The most common clinical signs are the development of subcutaneous xanthomas and lipemia retinalis (Ford RB, 1996). Also, the development of lipid granulomatas at trauma sites and abdominal organs could cause nerve damage resulting in loss of conscious proprioception and motor function (Case LP et al, 2011). 

There are dietary considerations to consider with LPL deficient cats.  Since chylomicrons also carry fat-soluble vitamins, LPL deficient cats have a diminished ability to uptake fat-soluble vitamins (Goldberg IJ et al, 2009).  These cats do not appear to have a specific risk factor for CaOx urolith formation nor a notable change in fecal microbial metabolites (Paßlack N et al, 2017).  Adequate dietary niacin for LPL deficient cats may also be important in reducing hypertriglyceridemia. Niacin increases HDL by selectively inhibiting hepatic diacylglycerol acyltransferase 2, a catalysis for the formation of triglycerides (Meyers CD et al., 2004).  Niacin also decreases fatty acid release from adipocytes and reduces VLDL produced from the liver (Nelson RW et al, 2003).

Studies on LPL

Since LPL deficient cats have a lipid and lipoprotein phenotype that predominantly parallels human with the same deficiency, studies have been conducted using them and genetically modified mice to better understand the pathobiology of LPL (Ginzinger DG et al, 1999).

LPL Location—
One study found when LPL was relatively increased in a specific tissue, there was more lipid delivered to that tissue.  For example, both the mice with LPL in muscle only and the mice with an increased ratio of myocyte LPL to adipocyte LPL had more myocyte lipid and a normal amount of adipocyte fat (Weinstock PH et al, 1997).

Hormones—
Studies have looked at the effect of certain hormones on LPL activity. The LPL response to feeding and fasting is tissue specific.  Insulin decreases expression of muscle LPL, but increase adipose tissue LPL activity (Goldberg IJ et al, 2009; Kiens B et al, 1989).  The hormone glucagon is anabolic to all tissue— increasing adipose tissue, muscle tissue, and myocardial LPL activity. Adrenaline too increases skeletal muscle and myocardial LPL (Kiens B et al, 1989).

Diet—
Macronutrients also have an effect on LPL activity and lipoprotein levels.  Analyzing fat, the consumption of saturated fatty acids lead to an increase in LDL concentrations compared with monounsaturated and polyunsaturated fatty acids (Brassard D et al, 2017).  There could be a small reduction in the risk of developing atherosclerosis by replacing saturated fatty acids with polyunsaturated fatty acids (Hooper L, 2015). An additional study found a high monounsaturated fatty acid diet increased LPL activity, increased HDL levels, and lowered total cholesterol levels.  Therefore, a high monounsaturated fatty acid diet could be less atherogenic, too (Schwingshackl L & Hoffmann G, 2013).  A few other studies looked at high carbohydrate diets that were low in fat.  They found high carbohydrate diets increased plasma triglyceride levels and decreased HDL levels, even compared to high saturated fatty acid diets (Kasim-Karakas SE et al, 2000; Thorning, TK et al, 2015).  There was more adipose LPL activity, and hence accumulation of body fat, in high carbohydrate diets compared to high fat diets (Goldberg IJ et al, 2009).

Conclusion

The proteins, cholesterols and triacylglycerol that make up lipoproteins are important for normal cell structure and function.   Lipoprotein imbalances can result in diseases like atherosclerosis or hepatic lipidosis or be the result of a genetic component like lipoprotein deficiency.  Environmental and genetic factors like diet, hormones, and enzyme concentration all impact lipoprotein forms and fat metabolism. Though we can’t control predisposed factors like genetics, manipulating controllable factors like diet and hormone sensitivity may help reduce risk of developing a fat metabolism imbalance.


References:

  • Backus RC, Ginzinger DG, Ashbourne Excoffon KJ, Clee SM, Hayden MR, Eckel RH, Hickman MA, Rogers QR. Maternal expression of functional lipoprotein lipase and effects on body fat mass and body condition scores of mature cats with lipoprotein lipase deficiency. Am J Vet Res. 2001 Feb;62(2):264-9.
  • Brassard D, Tessier-Grenier M, Allaire J, Rajendiran E, She Y, Ramprasath V, Gigleux I, Talbot D, Levy E, Tremblay A, Jones PJ, Couture P, & Lamarche B. Comparison of the impact of SFA's from cheese and butter on cardiometabolic risk factors: a randomized controlled trial. Am J Clin Nutr. 2017 Apr;105(4):800-809. doi: 10.3945/ajcn.116.150300.
  • Berg JM, Tymoczko JL, Stryer L. Biochemistry. 5th edition. New York: W H Freeman; Section 22.1 Triacylglycerols Are Highly Concentrated Energy Stores. Section 26.3 The Complex Regulation of Cholesterol Biosynthesis Takes Place at Several Levels. 2002.
  • Brown MS and Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science. 1986; 232:34–47.
  • Case LP, Daristotle L, Hayek MG, & Raasch MF. Canine and Feline Nutrition, A Resource for Companion Animal Professionals.  3rd ed. Marylands Heights, MO: Mosby, 2011.
  • Chapman MJ, Ginsberg HN, Amarenco P, Andreotti F, Borén J, Catapano AL, Descamps OS, Fisher E, Kovanen PT, Kuivenhoven JA, Lesnik P, Masana L, Nordestgaard BG, Ray KK, Reiner Z, Taskinen MR, Tokgözoglu L, Tybjærg-Hansen A, Watts GF, European Atherosclerosis Society Consensus Panel. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. European Heart Journal. 2011;32(11):1345–1361. doi:10.1093/eurheartj/ehr112
  • Christopher MM. Hyperlipidemia and other clinicopathologic abnormalities associated with canine hypothyroidism. Canine Pract 1997;22:37-38.
  • Clee SM, Bissada N, Miao F, Miao L, Marais AD, Henderson HE, Steures P, McManus J, McManus B, LeBoeuf RC, Kastelein JJ, & Hayden MR. Plasma and vessel wall lipoprotein lipase have different roles in atherosclerosis. J Lipid Res. 2000 Apr;41(4):521-31.
  • Dimski DS. Feline Hepatic Lipidosis. Semin Vet Med Surg (Small Anim). 1997 Feb;12(1):28-33.
  • Ford RB. Clinical management of lipemic patients. Compend Contin Educ Pract Vet. 1996;18:1053-1065.
  • Ginzinger DG, Clee SM, Dallongeville J, Lewis ME, Henderson HE, Bauje E, Rogers QR, Jensen DR, Eckel RH, Dyer R, Innis S, Jones B, Fruchart JC, & Hayden MR. Lipid and lipoprotein analysis of cats with lipoprotein lipase deficiency. Eur J Clin Invest. 1999 Jan;29(1):17-26.
  • Ginzinger DG, Lewis ME, Ma Y, Jones BR, Liu G, & Jones SD. A Mutation in the Lipoprotein Lipase Gene Is the Molecular Basis of Chylomicronemia in a Colony of Domestic Cats. J Clin Invest. 1996 Mar 1;97(5):1257-66.
  • Goldberg IJ, Eckel RH, & Abumrad NA. Regulation of fatty acid uptake into tissues: lipoprotein lipase- and CD36-mediated pathways” J Lipid Res. 2009 Apr;50 Suppl:S86-90. doi: 10.1194/jlr.R800085-JLR200.
  • Hooper L, Martin N, Abdelhamid A, & Davey Smith G. Reduction in saturated fat intake for cardiovascular disease. Cochrane Database Syst Rev. 2015 Jun 10;(6):CD011737. doi: 10.1002/14651858.CD011737.
  • Kasim-Karakas SE, Almario RU, Mueller WM, & Peerson J. Changes in plasma lipoproteins during low-fat, high-carbohydrate diets: effects of energy intake. Am J Clin Nutr. 2000 Jun;71(6):1439-47.
  • Kiens B, Lithell H, Mikines KJ, & Richter EA. Effects of insulin and exercise on muscle lipoprotein lipase activity in man and its relation to insulin action. Journal of Clinical Investigation. 1989;84(4):1124-1129.
  • Kim JY, Park JH, Jeong SW, Schellingerhout D, Park JE, Lee DK, Choi WJ, Chae SL, Kim DE. High Levels of Remnant Lipoprotein Cholesterol Is a Risk Factor for Large Artery Atherosclerotic Stroke. J Clin Neurol. 2011 Dec;7(4);203-9. doi: 10.3988/jcn.2011.7.4.203.
  • Mahley RW, Huang Y, Weisgraber KH. Putting cholesterol in its place: apoE and reverse cholesterol transport. Journal of Clinical Investigation. 2006;116(5):1226-1229. doi:10.1172/JCI28632.
  • Meyers CD, Kamanna VS, & Kashyap ML. Niacin therapy in atherosclerosis. Current Opinion in Lipidology. Dec 2004;15(6):659–65. 
  • Nelson RW & Elliot DA. Disorders of metabolism. In: Nelson RW, Couto CG, eds. Small animal internal medicine. 3rd ed. St. Louis, Mo: Mosby, 2003;822-827
  • Nordestgaard BG & Tybjaerg-Hansen A. IDL, VLDL, chylomicrons and atherosclerosis. Eur J Epidemiol. 1992 May;8 Suppl 1:92-8.
  • Paßlack N, Zentek J, Larsen JA, Westropp JL, & Fascetti AJ. Impact of hyperlipidaemia on intermediary metabolism, faecal microbial metabolites and urinary characteristics of lipoprotein lipase deficient vs. normal cats. J Anim Physiol Anim Nutr (Berl). 2017 May 11. doi: 10.1111/jpn.12721
  • Schwingshackl L & Hoffmann G. Comparison of effects of long-term low-fat vs high-fat diets on blood lipid levels in overweight or obese patients: a systematic review and meta-analysis. J Acad Nutr Diet. 2013 Dec;113(12):1640-61. doi: 10.1016/j.jand.2013.07.010.
  • Shelness GS, Sellers JA. From cholesterol transport to signal transduction: low density lipoprotein receptor, very low density lipoprotein receptor, and apolipoprotein E receptor-2. Biochim Biophys Acta. 2000;1529(1–3): 287–298.
  • Thorning, TK, Razian F, Bendsen NT, Astrup A, Tholstrup T, & Raben A. Diets with high-fat cheese, high-fat meat, or carbohydrate on cardiovascular risk markers in overweight postmenopausal women: a randomized crossover trial. Am J Clin Nutr. July 2015. doi: 10.3945/​ajcn.115.109116
  • Tsutsumi K. Lipoprotein lipase and atherosclerosis. Curr Vasc Pharmacol. 2003 Mar;1(1):11-7. doi: 10.1016/S0021-9150(03)00014-5.
  • Valtolina C & Favier RP. Feline Hepatic Lipidosis. Vet Clin North Am Small Anim Pract. 2017 May;47(3):683-702. doi: 10.1016/j.cvsm.2016.11.014.
  • Varbo A, Benn M, Tybjærg-Hansen A, Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG. Remnant cholesterol as a causal risk factor for ischemic heart disease. Journal of the American College of Cardiology. 2013;61(4):427–436. doi:10.1016/j.jacc.2012.08.1026.
  • Veltri BC, Backus RC, Rogers QR, & Depeters EJ. Adipose fatty acid composition and rate of incorporation of alpha-linolenic acid differ bt normal and LPL-deficient cats. J Nutr. 2006 Dec;136(12):2980-6.
  • Wang H & Eckel RH. Lipoprotein lipase: from gene to obesity. Am J Physiol Endocrinol Metab. 2009 Aug;297(2):E271-88. doi: 10.1152/ajpendo.90920.2008.
  • Wang L, Gill R, Pedersen TL, Higgins LJ, Newman JW, & Rutledge JC. Triglyceride-rich lipoprotein lipolysis releases neutral and oxidized FFAs that induce endothelial cell inflammation. J Lipid Res. 2009 Feb;50(2):204-13. doi: 10.1194/jlr.M700505-JLR200.
  • Weinstock PH, Levak-Frank S, Hudgins LC,  Radner H, Friedman JM, Zechner R, & Breslow JL. Lipoprotein lipase controls fatty acid entry into adipose tissue, but fat mass is preserved by endogenous synthesis in mice deficient in adipose tissue lipoprotein lipase. Proceedings of the National Academy of Sciences of the United States of America. 1997;94(19):10261-10266.

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