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Lipoproteins and Select Associated Health Issues

Written by: Elizabeth M.


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).

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).

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).

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’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).

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 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:

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).

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).

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).


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.


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