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Crystal structure of Escherichia coli-expressed Haloarcula marismortui bacteriorhodopsin digestions of lipids

Image: “Crystal structure of Escherichia coli-expressed Haloarcula marismortui bacteriorhodopsin I in the trimeric form.” by Shevchenko V, Gushchin I, Polovinkin V, Round E, Borshchevskiy V, Utrobin P, Popov A, Balandin T, Büldt G, Gordeliy V – PLoS ONE (2014). License: CC BY 4.0

What are Lipids?

Lipids consist of triglycerides, cholesterol, phospholipids, fat-soluble vitamins (vitamin A, D, E, and K), and fatty acids. Lipids are lipophilic, which means that they do not dissolve in water. Absorption of lipids is equally important as other nutrients for the derivation of energy required for various cellular functions. Therefore, a few detours are necessary to take in those fats into our hydrophilic body.

Triglyceride Molecule

Image: “Triglyceride Broken Down into a Monoglyceride” by Phil Schatz, License: CC BY 4.0

Lipids are an essential part of our nutrition. Besides vitamin A, E, and K, the essential fatty acids, alpha-linoleic acid, and alpha-linolenic acid also have to be absorbed through food from outside the body to be used in metabolism; but how can a lipophilic nutrient be ingested and used by a hydrophilic system such as our human body? For lipids to be reabsorbed into the blood circulation, they have to be degraded by enzymes into free fatty acids and diglycerides. This degradation is called hydrolysis. However, gastric lipases, i.e. the enzymes that degrade fats, are proteins and thus cannot simply attach to the lipid and start working. A bit of preliminary work is necessary, like the formation of micelles and the addition of bile acid.

Preliminary Work for Lipid Digestion and the Reabsorption of Lipids

The digestion of lipids starts in the oral cavity. Teeth and saliva reduce a large piece of food to small pieces and a so-called bolus, a round mass of masticated food, is formed. The 1st digestive enzymes are already contained in the saliva, as, e.g., the lingual lipase. This enzyme is secreted by glands found in the tongue. The lingual lipase is especially active at low pH levels. The gastric lipase, too, is active in an acid environment. It acts on fat and separates them from the watery components of food, turning them into tiny fat droplets.

Both lipases release mostly short-chain fatty acids like those contained in, e.g., ester bonds in triglycerides of milk fat. Emulsification of dietary fat and fat-soluble vitamins happens majorly in the stomach. Short-chain fatty acids can be reabsorbed directly into the venous blood of the stomach and be taken up by the bloodstream. This is especially important in infant nutrition because the pancreas lipase is not yet fully developed in infants. Lipid absorption in adults, by contrast, occurs mainly in the duodenum and upper jejunum.

Through the process of mastication in the oral cavity and gastric motility, the food is reduced to small pieces and mixed thoroughly. This process induces an emulsion, which means that lipids form tiny droplets, which are then distributed in the aqueous surrounding, providing a large target area for lipases. Lipids are broken into triglycerol and diglycerides to fatty acids by these enzymes.

The main site of reabsorption of fats is the duodenum and the upper part of the jejunum. On its way there, the half-digested food mass (now called chyme) has already been comminuted. However, for reabsorption, it is necessary to break down the triglycerides into free fatty acids and monoglycerides. Within the duodenum, pancreatic juice and bile acid are added to the chyme. The secretion from the pancreas contains the pancreas lipase that is activated by neutral to alkaline pH values (pH 7–8).

Bile acid contains bile salts and bile acids. Bile acids attach to the fat particles, which results in a negative surface charge. This process facilitates the binding of a colipase to the triglycerides. The colipase acts as a bridge by binding the enzyme that is necessary for hydrolysis: the pancreas lipase. Now, the pancreas lipase can start to break down the interesterified fats and split off the fatty acids on the boundary surface of the lipid-water suspension.

In a continuous process, increasingly small lipophilic parts are produced. Aided by calcium, the released products, and bile acids spontaneously form micelles. Micelles are particles that enclose all the lipophilic elements (cholesterol, phospholipids, free fatty acids, etc.) which is why they are also referred to as mixed micelles.

The pancreatic juice also contains other lipases that all function, based on the same principle: the cholesterol esterase (also referred to as carboxylesterase) hydrolyzes cholesterol esters; phospholipases A1 and A2 hydrolyze the phospholipids.

After the lipids have been hydrolyzed by the pancreas lipases, the particles are small enough to be reabsorbed into the cells of the mucosa.

Absorption of Lipids in the Lymphatic System and the Formation of Chylomicrons

The absorption of mixed micelles from the lumen of mucosa cells is a passive process that occurs along a concentration gradient with the help of gut motility through the brush border membrane. Mucosa cells contain the fatty acid-binding protein (FABP), then the ‘reassembly of lipids’ follows inside the smooth endoplasmic reticulum.

Structure of a Lipoprotein

Image: “Structure of a Lipoprotein” by AntiSense, License: CC BY-SA 3.0

Once more triglycerides are formed through the esterification of free fatty acids and glycerides. Phospholipids and cholesterol are resynthesized as well. The newly built lipids migrate through the cisternae of the Golgi apparatus to the rough endoplasmic reticulum where apolipoproteins are added. The so-called chylomicrons are formed with apolipoproteins 48 and A1.


Image: “Chylomikron-Struktur” by Xvazquez, License: CC BY 3.0

Chylomicrons are large lipoproteins that have a lipophilic interior and a surface made of glycoproteins, which means that they are amphiphilic. Lipoproteins are formed when triglycerols, cholesterol, and phospholipids join together with a protein barrier. This way, the lipids can be transported through a hydrophilic surrounding and the apoprotein part allows for specific bonds to be made, as, e.g., with enzymes that carry out further degradation and conversion processes.

Chylomicrons are the lipoproteins with the least density and the highest particle volume because their protein part is relatively small and the lipid part (which is composed of various lipids such as triglycerides, phospholipids, free fatty acids, etc.) is relatively large. They transport fat to different destinations of the body through the water-based environment.

From the mucosa cells, the chylomicrons 1st pass into the lymphatic system. The detour via the lymphatic system allows the body to 1st use other energy sources like carbohydrates, which are also abundantly present in the body after a meal. Therefore, lipids can bypass the liver entirely via the lymphatic system before being used as an energy supply later on.

The fat which is poorly absorbed is cholesterol in comparison to triglycerides or phospholipids. Dietary fiber found in fresh fruits, vegetables, and oats hinders their absorption from the intestine and excrete them from the colon thus reducing blood cholesterol.

Inside the bloodstream

Chylomicrons pass through the ductus thoracicus into the vena cava, where an active exchange of apolipoproteins takes place. Apolipoprotein A1 (ApoA1) is passed on to the lipoprotein HDL (this lipoprotein has a particularly high protein part and a small lipid part, which means it is rather small and has a high density, thus high-density lipoprotein = HDL). In exchange for ApoA1, the chylomicron receives the apolipoproteins C2 and E from HDL. After esterification of cholesterol, HDL is transferred to LDL for utilization into tissues.

The chylomicron now floats with its newly acquired apolipoproteins inside the bloodstream. Specific endothelial cells (e.g., the muscle or heart) contain lipoprotein lipase (LPL) that can bind to the apoprotein C2 of the chylomicron and activate the lipase. Here LDL is rich in cholesterol esters. LPL then hydrolyzes triglycerides from inside the chylomicron and forms free fatty acids and glycerin. The free fatty acids now act as an energy supply for the target cell.

Breakdown of Fatty Acids

Image: “Breakdown of fatty acids” by Phil Schatz, License: CC BY 4.0

During this process, apoprotein C2 is lost. However, the remaining fragments, referred to as chylomicron remnants, do still have their apolipoprotein E (ApoE). The matching counterpart is found in the endothelial cells of the liver. The chylomicron remnants are absorbed into the hepatocytes via ApoE-receptors. The remaining lipophilic particles are metabolized inside the hepatocytes, packaged once more and, in the form of VLDL (the 2nd largest lipoprotein), sent back on their journey through the bloodstream after utilization in the extra-hepatic tissues.

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