Fat Metabolism

What is fat metabolism? Fat/lipid metabolism is digestion of fat, absorption, liver synthesized lipoproteins, and pile acid recycling.

Fat digestion, absorption & assimilation

Lipid metabolism has a close association with the carbohydrate metabolism. The product of carbohydrate digestion is glucose. The excess glucose converted into glycogen. And the remaining glucose stored as fat for future energy needs.

Fats also called as lipids. Lipid is the common word used to describe fats, oils, waxes and other related compounds.

Dietary cholesterol represents only 1/3 of your total cholesterol requirements. Remaining cholesterol is from liver production.

The cholesterol from the diet (exogenous) is just 25% of the daily cholesterol need. This exogenous cholesterol might be 300 to 500mg. The remaining 75% might be 800 to 1,200 mg synthesized by the body (endogenous). Endogenous synthesis is by the liver and body cell. The cholesterol produced by the body increases when you eat low cholesterol foods. If you eat more cholesterol food, cholesterol production by the body decreases. This mechanism explains, why a low-fat diet, lower blood cholesterol just a few percent.

Types of Fats

Before learning about fat metabolism, first, you should know different types of fats.

Fats are of three groups, they are simple, compound, and derived lipids.

1. Simple Lipids are triglycerides, comprised of three fatty acids joined to a glycerol backbone. The dietary fats and the stored fats are mostly (about 98%) triglycerides. Simple or neutral fats are two subtypes saturated and unsaturated fatty acid. Saturated fats are fats with all its carbon atoms saturated with hydrogen atoms. Additionally, it does not have double bonds between carbon atoms. This structure makes it harder to breakdown. Saturated fats are in solid form at room temperature. Examples of saturated fats are an animal (beef) meat and dairy (milk, butter) products. Unsaturated fats are fats with at least one double bond within the fatty acid chain. This double bond makes it easier to breakdown. Unsaturated fatty acids are in plant sources.
2. Compound lipid is a triglyceride in combination with other chemicals. Phospholipids have one or more fatty acids along with a phosphorus group and a nitrogen base. Glycolipids have fatty acids along with glucose & nitrogen. Lipoproteins have the combination of lipids with proteins. Lipoproteins are the body's lipid transport system.
3. Derived lipids have hydrocarbon rings instead of chains. Cholesterol is a waxy, fat-like substance in every body cell and many foods.

Apolipoproteins are proteins; lipoproteins formed by the combination this protein and lipids.

Lipoproteins

Lipoproteins consists of triglycerides, cholesterols, phospholipids and proteins (apolipoproteins).

The level of fats in a lipoprotein decides its density; low density has low levels of lipids, and vice versa. You can differentiate lipoproteins based on their density and the type of apolipoproteins. Low-density lipoprotein has excess lipids compared to protein. The four types of lipoproteins are chylomicrons, very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL).  

1. Chylomicrons produced by enterocytes are from lipids absorbed in the small intestine. Chylomicrons transport triglycerides from intestines to liver, skeletal muscle & adipose tissue. Body consumes fat by the lipoprotein lipase action (enzyme on the endothelial cells). This enzyme breaks triglycerides into fatty acids and monoglycerides.
2. The liver synthesizes VLDL (very low-density lipoprotein). Like chylomicrons, VLDL deliver triglycerides to cells in the body.
3. IDL is an intermediate between VLDL and LDL. As VLDL particles lose its triglycerides to form IDL.
4. LDL transport cholesterol from the liver to the body cells. Body cell membranes use it for energy or synthesize steroid hormones. Triglycerides stripped from the VLDL becomes denser, and liver remodels it into LDL.
5. HDL synthesized and secreted by the liver and small intestine. HDL collects excess cholesterol from the tissues and then deliver it to the liver. This transporting of cholesterol back to the liver is known as reverse cholesterol transport.

Lipid Homeostasis

If you increase the cholesterol intake, your body lowers cholesterol synthesis and reabsorption. Conversely, if you decrease the cholesterol intake, your body increase cholesterol synthesis and reabsorption.

Reabsorption of the cholesterol is the dominant source of the cholesterol in the body. Remaining cholesterol requirement is fulfilling by synthesize or absorb from the food.

Lipid metabolism has three main pathways; they are

1. Exogenous pathway – Exogenous refers to dietary absorption (from food) cholesterol through the intestine.
2. Endogenous pathway – Endogenous refers to be liver produced (hepatic-derived - liver produced) lipoproteins.
3. Reverse cholesterol transport - transfer of unused cholesterol from the cells back to the liver.

Exogenous pathway of lipid metabolism

Fat is an important energy source derived from foods. More than 95% of dietary fat is long-chain triglycerides. The remaining being phospholipids (4.5%) and sterols. Most body cell in our body is capable of producing cholesterol on its own. Only a few cells need cholesterol supply.

Fat digestion consists of three steps, they are emulsification, hydrolyzes, and break down. Fats in the food is emulsifying by the bile salt. Emulsified fat is hydrolyzing by the lipase. Finally fat broken down into monoglycerides and fatty acids.

Fat digestion occurs almost completely in the small intestine. The enzyme pancreatic lipase splits bonds between fatty acids and glycerol. It results in monoglyceride and free fatty acids.

Bile acid is crucial for the fat digestion. Cholesterol is necessary for the bile acid synthesis. Reabsorption of bile acids during the metabolic recycling.

Proper fat digestion requires complete emulsification of lipids. This emulsification facilitates an increase in the exposing area for the lipase activity. Bile salt contains bile acid, cholesterol, and phospholipids (lecithin). Bile acid structure is like a detergent molecule. This structure help disperses fats into smaller packets called emulsification (fat water mixer).  

Triglyceride digestion involves gastric lipase, emulsification by bile, and pancreatic lipase. The resultant product is monoglycerides & free fatty acids.

Similarly, cholesterol esters in the diet undergo de-esterification to produce free cholesterol.

Absorbed monoglycerides and fatty acids passed through the epithelial cells and formed into chylomicron. The Chylomicrons are lipoproteins that contain triglycerides and other lipids (cholesterol, fat-soluble vitamins, etc.). The chylomicrons reach the bloodstream through the lymphatic vessels.

The apolipoproteins predominated in the chylomicrons are apoE & apoB-48. Additionally, it contains apoA-I, apoA-II, and apoA-IV.

ApoA-I removes oxidized phospholipids from oxidized LDLs (oxLDLs). ApoA-II reduces LDL oxidation. ApoA-IV has anti-oxidant, anti-inflammatory and anti-atherosclerotic actions. ApoA-IV secrets by the small intestine and synthesized in the gut. And stimulated by active lipid absorption. ApoE has anti-atherosclerotic activity.

The chylomicrons have triglycerides (88%), the remaining being phospholipids, cholesterol, and cholesteryl esters. Lipase helps adipocytes & muscle cells to consume chylomicron's triglycerides for energy or storage. Chylomicrons provide triglycerides and receive cholesterol esters from the HDL. As a result, chylomicron remnants reduced in size and enriched in cholesteryl esters. Liver received the energy depleted cholesterol-rich chylomicron and excreted it from the body.

Exogenous Pathway in short:

1. Gastric lipase, bile salt, and lipase broke down fats into fatty acids and monoglycerides.
2. Digestive tract absorbs lipids, convert into chylomicrons, and reach the bloodstream via lymphatic vessels.
3. Lipase in the peripheral tissues (e.g. adipose) broken down chylomicron's lipids into fatty acids & glycerol.
4. By losing its lipids, chylomicrons become smaller called chylomicron remnants. Additionally, as a by-product, it produces empty HDL.
5. Chylomicrons reached the liver and removed by the apoE-mediated process.

Endogenous pathway of lipid metabolism

 VLDL is the endogenous (liver synthesized) lipoprotein. VLDL is similar to the exogenous (dietary absorbed) lipoprotein Chylomicrons. Between meals or during fasting, VLDL releases into the bloodstream. After VLDL give up its lipids to tissues, it becomes IDL then converted to LDL by the liver.

Liver produced lipoprotein very low-density lipoproteins (VLDL) transports lipids via the blood circulation. Factors affecting hepatic lipoprotein synthesis can lead to elevated plasma cholesterol and triglyceride levels. VLDLs contain cholesterol, cholesteryl esters, and the apoproteins (apoB-100, apoC-I, apoC-II, apoC-III and apoE).

Like chylomicrons, VLDLs transport triglycerides for energy to adipose tissue, skeletal muscle, and heart. This process results in the formation of intermediate density lipoprotein (IDL). The liver removes this IDL via apoE receptors. IDL are cholesterol-rich VLDL remnants. ApoE in IDL makes it high affinity for the LDL receptor on cells (hepatocytes and adrenal cortex).

IDLs triglycerides loss and transfer of apoE to HDL results in cholesterol-ester-rich LDLs. This LDL has apoB100 as a sole apolipoprotein. Low-density lipoproteins (LDL) is the products of VLDL and IDL metabolism. Of all lipoproteins, LDLs are the most cholesterol-rich. The LDL received back by the liver. Liver esterifies LDL cholesterol into cholesteryl ester. And it is converted into bile acids or vitamin D. LDL cholesterol is consume by the peripheral tissues. These peripheral tissues are adrenals, testes, ovaries, and liver. LDL Cholesterol also aids as a precursor for steroid hormones. 

The size of LDL particles varies from large buoyant to small dense. Small dense LDL is rich in cholesterol esters. These cholesterol esters have an association with metabolic disturbances (e.g. hypertriglyceridemia & insulin resistance). This LDL is especially atherogenic. The increased atherogenicity of small LDL derived from less efficient hepatic LDL receptor binding. Thus, prolong its presence in circulation, so increased exposure to endothelium & oxidation.

Endogenous Pathway in short

1. Liver produced lipids & cholesterols packed into VLDL's.
2. Between meals, liver produced VLDL released into the bloodstream. This VLDL will reach the peripheral tissues.
3. VLDL reaches the lipoprotein lipase expressing tissues in the muscle & adipose. Lipase breaks down VLDL into glycerol & fatty acids.
4. Once the VLDL lost most of its fat, it becomes smaller in size called an IDL. Empty HDL produced as a byproduct.
5. IDL reaches liver and lipase broken down it into LDL after triglycerides removal.

LDL’s contains high cholesterol and little fatty acids or glycerol. LDL circulates and absorbed by various tissues. Excess LDL absorbed by the liver.

Reverse cholesterol transport

Reverse cholesterol pathway play an important role in cholesterol homeostasis. Excess cholesterol in the tissues, taken back to the liver by the HDL, and excreted in the feces.

Recent research suggests cholesterol in the circulation directly secret into the intestine.  And the liver is not involved in this process. HDL formation begins by the synthesis of apoAI by the liver and intestine.

The role of HDL in reverse cholesterol transport is atheroprotective. It prevents the development of atherosclerotic lesions. Additionally, HDLs exhibits anti-inflammatory, antioxidant, vasodilatory, anti-apoptotic, anti-thrombotic, and anti-infectious properties. The small dense HDL3 particles are the most beneficial.

These HDLs are devoid of any cholesterol, cholesteryl esters, lipids, and any other proteins. In HDLs, ApoA-I is the predominant apoprotein; it is about 70% of the total protein mass. Additionally, it contains apoproteins apoC-I, apoC-II, apoD, apoE, apoF, apoM, and apoO. HDLs contains enzymes that have antioxidant activities.

The cholesterol transfer from macrophages involves apoA-I. This transfer results in pre-β HDLs formation. These pre-β HDL enlarges with the cholesterol uptake and leads to HDL2 & HDL3 particles. HDL involved in the transfer of cholesterol ester to VLDL, IDL, and LDL.