METABOLISM OF TRIGLYCERIDES

DR.J.SIVAKUMARASSISTANT PROFESSOR

Lipids have a varied structure but all have the following properties in common:-Insoluble in waterSoluble in organic solvents

The three main groups of lipids are:-TriglyceridesPhospholipidsSteroids

INTRODUCTION

Triglycerides Triglycerides consist of a

single glycerol molecule and three fatty acids.

Triglycerides form by condensation (dehydration) reactions between the hydroxyl (OH) groups of the glycerol and the carboxyl (COOH) group of three fatty acids.

Triglycerides are esters being derived from an alcohol and a fat

CONTD.. Glycerol (blue) is an

alcohol derivative of glyceraldehyde and has three hydroxyl groups. It acts as the backbone of the structure.

Fatty acids (red) – there are more than 70 types of fatty acid but they all have long hydrocarbon tails and a terminal carboxyl group (COOH). The variety of fatty acids determine the properties of each triglyceride.

Vegetable oils are triglycerides that are liquid at room temperature due to their higher unsaturated or shorter-chain fatty acids.

Natural fats have D-configurationUsually R1 and R3 are saturated and R2 is

unsaturatedNatural fats are mixture of two or more

simple triglycerides

Nomenclature and Structure

Stored in anhydrous state Non-polar Provide ~ 6 times energy of hydrated glycogen

◦Stored in large quantities in cells Non-reactive with other cell components Segregated into lipid droplets Do not affect osmolarity of cytosol

triglycerides

Triglycerides are also the major form of stored energy in the body

Hormones (glucagon, epinephrine, ACTH) trigger the release of fatty acids from adipose tissue.

Contd..

Used for > half the energy in: Liver Heart Resting skeletal muscle

Hibernating animals and migrating birds

Higher plants: Do not depend on fats for energy

Germinating seeds

Contd..

• Cholesterol, Triglycerides and Phospholipids• Transported by lipoproteins• Cholesterol can be free or esterified• Triglycerides must be degraded to be

absorbed by cells

transport

Liver and adipose tissue are the major sites of triacylglycerol (TAG) synthesis. The TAG synthesis in adipose tissue is for storage of energy whereas in liver it is mainly secreted as VLDL and is transported.

The TAG is synthesized by esterification of fatty acyl CoA with either glycerol-3-phosphate or dihydroxy acetone phosphate (DHAP).

synthesis

Contd.. The glycerol part of

the fat is derived from the metabolism of glucose. DHAP is an intermediate of glycolysis.

Glycerol-3-phosphate may be formed by phosphorylation of glycerol or by reduction of dihydroxy acetone phosphate (DHAP)

In adipose tissue, glycerol kinase is deficient and the major source is DHAP derived from glycolysis.

In liver, glycerol kinase is active. The fatty acylCoA molecules transfer the fatty acid to the hydroxyl groups of glycerol by specific acyltransferases.

Contd..

Minor pathway In addition to these

two pathways, in the intestinal mucosal cells the TAG synthesis occurs by the MAG pathway.

The 2-MAG absorbed is re-esterified with fatty acylCoA to form TAG.

Under conditions of fasting, it is seen that synthesis of triacylglycerol occurs side by side with lipolysis, since the free fatty acid level is high in plasma.

In the fasting state, the glycerol phosphate is derived from dihydroxyacetone phosphate formed during gluconeogenesis.

Fasting state

The activity of the enzyme PEPCK is enhanced in liver and adipose tissue during conditions of fasting, so that glycerol phosphate is available to esterify and store the excess fatty acid mobilized.

Contd..

Esterification of fatty acylCoA with glycerol phosphate to form triacylglycerol occurs at a rapid rate during the fed state.

The glycerol phosphate is derived from the metabolism of glucose in the fed state by channeling dihydroxy acetone phosphate, an intermediate of glycolysis.

Fed state

Pancreatic lipase can easily hydrolyze the fatty acids esterified to the 1st and 3rd carbon atoms of glycerol forming 2-monoacylglycerol and two molecules of fatty acid.

Then an isomerase shifts the ester bond from position 2 to 1. The bond in the 1st position is then hydrolyzed by the lipase to form free glycerol and fatty acid

Digestion of Triacylglycerols

Contd..

The binding of co-lipase to the triacylglycerol molecules at the oil water interface is obligatory for the action of lipase.

The co-lipase is secreted by the pancreas as an inactive zymogen (molecular weight 11,000). It is activated by trypsin.

Contd..

The adipose tissue serves as a storage site for excess calories ingested. The triglycerides stored in the adipose tissue are not inert.

They undergo a daily turnover with new triacylglycerol molecules being synthesized and a definite fraction being broken down.

Metabolism of adipose tissue

The dietary triglycerides transported by chylomicrons and the endogenously synthesized triglycerides from liver brought by VLDL are both taken up by adipose tissue and esterified and stored as TAG.

The lipoprotein molecules are broken down by the lipoprotein lipase present on the capillary wall.

Adipose Tissue in Well-fed Condition

In well fed condition, glucose and insulin levels are increased. GluT4 in adipose tissue is insulin dependent. Insulin increases the activity of key glycolytic enzymes as well as pyruvate dehydrogenase, acetyl CoA carboxylase and glycerol phosphate acyl transferase.

The stimulant effect of insulin on the uptake of glucose by adipose tissue, on the glycolysis and on the utilization of glucose by HMP pathway also enhances lipogenesis

Contd..

Contd.. Insulin also causes

inhibition of hormone sensitive lipase, and so lipolysis is decreased

TAG from the adipose tissue is mobilized under the effect of the hormones, glucagon and epinephrine.

The cyclic AMP mediated activation cascade enhances the intracellular hormone sensitive lipase.

The phosphorylated form of the enzyme is active, which acts on TAG and liberates fatty acids.

Adipose Tissue in Fasting Condition

Under conditions of starvation, a high glucagon, ACTH, glucocorticoids and thyroxine have lipolytic effect.

The released free fatty acids (FFA) are taken up by peripheral tissues as a fuel.

Contd..

Lipolysis is enhanced and high FFA level in plasma is noticed in diabetes mellitus. Insulin acts through receptors on the cell surface of adipocytes.

These receptors are decreased, leading to insulin insensitivity in diabetes.

Adipose Tissue and Diabetes Mellitus

Increased mobilization of fatty acids from adipose tissue and the persistently high free fatty acid levels in the presence of hyperinsulinemia stimulates synthesis of triacylglycerol.

The overproduction of TAG leads to increased release of VLDL from liver causing hypertriglyceridemia

Contd..

The fat content of the adipose tissue can increase to unlimited amounts, depending on the amount of excess calories taken in. This leads to obesity.

A high level of plasma insulin level is noticed. But the insulin receptors are decreased and there is peripheral resistance against insulin action.

Adipose Tissue and Obesity

There are two types White adipose tissue Brown adipose tissue

Types

It is mainly concerned with energy storage. It is made up of spherical cells, with very few mitochondria. The triglycerides form the major component of white adipose tissue (about 80%) with oleic acid being the most abundant fatty acid (50%).

White Adipose Tissue

Brown adipose tissue is involved in thermogenesis. Brown adipose tissue cells are polygonal with more abundant cytoplasm. The brown color is due to the presence of numerous mitochondria.

It is primarily important in new born human beings and adult hibernating animals.

Brown adipose tissue

Thermogenesis is a process found in brown adipose tissue. It liberates heat by uncoupling oxidation from phosphorylation.

So energy is released as heat, instead of trapping it in the high energy bonds of ATP by the action of the uncoupling protein, thermogenin.

Contd..

Liver produces fatty acid and TAG (triacylglycerol), which is transported as VLDL (very low density lipoprotein) in the blood. The fatty acids from VLDL are taken up by adipose tissue with the help of lipoprotein lipase, and stored as TAG.

This neutral fat is hydrolysed by hormone sensitive lipase into NEFA, which in the blood is carried by albumin. The NEFA is utilized by the peripheral tissues, excess of which can be taken up by liver cells. Thus there is a constant flux of fat molecules from liver to adipose tissue and back

Liver-Adipose Tissue Axis

Fatty liver refers to the deposition of excess triglycerides in the liver cells. The balance between the factors causing fat deposition in liver versus factors causing removal of fat from liver, determines the outcome.

FATTY LIVER

Causes of fat deposition in liver 1. Mobilization of NEFA from adipose tissue. 2. More synthesis of fatty acid from glucose.

Reduced removal of fat from liver 3. Toxic injury to liver. Secretion of VLDL

needs synthesis of apo B-100 and apo C. 4. Decreased oxidation of fat by hepatic

cells.

Causes

Excessive Mobilization of Fat

Excess Calorie Intake

Toxic Injury to Liver

Alcoholism

Contd..

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease, where fat accumulates in hepatocytes. High fat diet and uncontrolled diabetes mellitus are the most common causes.

As it is progressed, inflammatory reaction occurs, which is then termed as nonalcoholic steatohepatitis (NASH).

Non-alcoholic Fatty Liver Disease

Fat molecules infiltrate the cytoplasm of the cell (fatty infiltration). These are seen as fat droplets, which are merged together so that most of the cytoplasm becomes laden with fat.

The nucleus is pushed to a side of the cell, nucleus further disintegrated (karyorrhexis), and ultimately the hepatic cell is lysed.

As a healing process, fibrous tissue is laid down, causing fibrosis of liver, otherwise known as cirrhosis. Liver function tests will show abnormal values.

Fatty Liver Progresses to Cirrhosis

They are required for the normal mobilization of fat from liver. Therefore deficiency of these factors may result in fatty liver.

They can afford protection against the development of fatty liver.

Choline: Feeding of choline has been able to reverse fatty changes in animals.

Lecithin and methionine. They help in synthesis of apoprotein and choline formation.

The deficiency of methyl groups for carnitine synthesis may also hinder fatty acid oxidation.

Lipotropic Factors

Vitamin E and selenium give protection due to their antioxidant effect.

Omega-3 fatty acids present in marine oils have a protective effect against fatty liver.

Contd..

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