SHIVAGOVINDAN K.PMSC, MEDICAL BIOCHEMISTRY

Lipoprotein, lipid transport and Hormonal influence on

lipid metabolism

Plasma Lipoproteins Structure

LP core Triglycerides Cholesterol esters

LP surface Phospholipids Proteins cholesterol

Overview of Lipoproteins

There are many types of apolipoproteins

Apoprotein Lipoproteins Function(s)

Apo A-I HDL, chylomicrons 1) Major structural protein of HDL2) Activator of LCAT

Apo A-II HDL, chylomicrons Unknown

Apo B-100 VLDL, IDL, LDL 1) Secretion of VLDL from liver 2) Structural protein of VLDL, IDL, and HDL 3) Ligand for LDL receptor (LDLR)

Apo B-48 Chylomicrons, remnants

Secretion of chylomicrons from intestine; lacks LDLR binding domain of Apo B-100

Apo C-I Chylomicrons, VLDL, IDL, HDL

Modulator of hepatic uptake of VLDL and IDL (also involved in activation of LCAT)

Apo C-II Chylomicrons, VLDL, IDL, HDL

Activator of LPL

Apo C-III Chylomicrons, VLDL, IDL, HDL

Inhibitor of LPL activity

Apo E Chylomicrons, VLDL, IDL, HDL

Ligand for binding of IDL & remnants to LDLR and LRP

Hormonal control of lipid digestion

The dietary triacylglycerol, cholesteryl esters, and phospholipids in small intestine are enzymically degraded by pancreatic enzyme whose secretion is hormonally controlled.

Cells in the mucosa of the jejunum and lower duodenum produce small peptide hormone cholecystokinine (pancreozymin) in response to the presence of the lipids and partially digested proteins entering these regions of the upper small intestine.

Contd..

This hormone acts on gallbladder (release bile) and on exocrine cells of pancreas (release digestive enzymes)

It also decrease gastric motility, resulting in slower release of gastric contents into small intestine.

Secretin, a small peptide hormone from intestinal cells produced in response to low pH of the chyme entering the intestine.

Hormones regulate lipogenesis

Insulin stimulates lipogenesis by increased transport of glucose into cell (adipose tissue), thereby increasing pyruvate for fatty acid synthesis and glycerol 3 phosphate for esterification of the newly formed fatty acid.

In adipose tissue, insulin activates (dephoshorylase) PDH through protein phoshatase, where acyl coA and pyruvate inactivates (phosphorylase) PDH through PDH kinase.

Contd..

Insulin activates acetyl-coA carboxylase through dephosphorylation by protein phosphatase. Acetyl-coA carboxylase is also regulated by reversible phosphorylation.

Insulin inhibits lipolysis in adipose tissue by decreasing intracellular level of CAMP. This reduces the concentration of plasma FFA and therefore long chain acyl coA, and inhibitor of lipogenesis.

Contd..

glucagon and epinephrine inhibit acetyl coA carboxylase and lipogenesis by increased CAMP, allowing CAMP-dependent protein kinase to inactivate the enzyme by phosphorylation.

protein kinase dependent 5’-AMP will also inactivate this enzyme.

Hormone regulate, fat mobilization

Insulin enhance the uptake of glucose into adipose cells via GLUT 4 transporter.

Insulin activates acetyl coA carboxylase by increasing PDH and glycerol phosphate acyl transferase,which enhance fatty acid and acyl glycerol synthesis.

Several hormones promote lipolysis

Hormones such as epinephrine, glucagon, ACTH, α and β MSH, TSH, GH and vasopressin promote lipolysis by activating hormone sensitive lipase.

Glucorticoids and thyroid hormone is required for lipolytic process.

Contd..

cAMP activate hormone-sensitive lipase, which influence lipolysis.

Catecholamine and epinephrine promote lipolysis by stimulating the activity of adenyl cyclase.

Insulin, nicotinic acid and PG E1 inhibit lipolysis acting on adenyl cyclase.

Contd..

CAMP is degraded to 5’-AMP by enzyme cyclic 3’,5’- nucleotide phosphodiesterase. This enzyme is inhibited by methylxanthines such as caffeine and theophylline.

Caffeine present in coffee, which elevates FFA in humans.

Contd..

Glucocorticoids promote lipolysis via cAMP independent pathway, inhibited by insulin and also by transcription of genes involved in the cAMP signal cascade, which help to explain the role of the pituitary gland and the adrenal cortex in enhancing fat mobilization.

ATP

cAMP

5’ AMP

Adenylyl cyclase

Phosphodiestrase

HORMONAL SENSITIVE

LIPASE

HORMONAL SENSITIVE

LIPASE

cAMP Dependent PK Lipase Phosphatase

Pi

HORMONAL SENSITIVE

LIPASE

2 MAG LIPASE

ATP

ADPTAG

FFA + DAG

FFA + MAG

FFA + MAG

FFA + DAG

FFA + GLYCEROL

+

Lipid absorption:

Lipids degraded by pancreatic lipase to FFA, free cholesterol, 2MAG. These together with bile salts form mixed micelles, which are soluble in the aqueous environment of the intestinal lumen.

Exogenous Lipid Transport

Exogenous pathway

Dietary lipids absorbed by intestine, transport to liver and peripheral cells, mediated by chylomicrons

HDL acquire apolipoprotein such as Apo E and C.

Apo C II is activator and apo C III is inhibitor of lipoprotein lipase, which hydrolyases TGL on chylomicrons to generate FFA and glycerol.

Contd..

During lipolysis chylomicrons are converted to chylomicron remnant particles with transfer of lipid and apolipoprotien onto HDL.

Chylomicron remnants are taken up by liver cells through Apo E and Apo B48 with specific remnant receptor.

In liver, chylomicron remnants are degraded by lysosomal enzymes to release FFA, free cholesterol and amino acid.

Ch

ylo

mic

ron

m

etab

olis

m

Endogenous Lipid Transport

Endogenous pathway:

Transfer the hepatic derived lipids TGL to peripheral cells, mediated by apolipoprotein B100.

It refers to hepatic secretion and metabolism of VLDL to IDL and LDL.

VLDL (55% TGL by mass) consists of apo B100 with same apoE and C secreted by liver.

Contd..

The packaging of hepatic TGL with nascent VLDL (apo B100, cholesteryl esters, PL and vitamin E) requires the action of enzyme microsomal transfer protein.

VLDL undergoes lipolytic process similar to chylomicrons on apoC II, activated by lipoprotein lipase to form VLDL remnant which on further lipolysed to LDL.

VL

DL

metab

olism

contd..

LDL cholesterol cleaved by LDL receptor, which mediate endocytosis in liver.

Lipoprotein(a) is lipoprotein similar to LDL in lipid and protein composition, but contain additional apolipoprotein(a).

Apo(a) is synthesized in liver and attached to Apo B100 by disulphide linkage.

Contd..

Before undergoing complete lipolysis half of apo B100 are removed by hepatic remnant receptors and converted to LDL.

TGL on LDL is further depleted by cholesterol ester transfer protein (CETP) which removes TGL from LDL and exchange cholesterol esters from HDL.

Cholesterol returned to liver for lipoprotein secretion and bile production.

Intracellular – cholesterol pathway:

This pathway represents homeostatic mechanism that the cells use to maintain cholesterol balance.

Free cholesterol derived from degraded LDL ,used for membrane biosynthesis.

Excess cholesterol is converted to cholesteryl esters by acyl-coA: cholesterol acyl transferase (ACAT), regulated by LDL receptor.

Contd..

An alternative route for removal of LDL via reticuloendothelial system collectively termed as scavenger cell pathway.

The rate of LDL receptor synthesis increase by thyroxine , estrogen and decrease with age.

HMG-coA reducatase , regulate cholesterol synthesis. Which is lowered by statin type drugs are down regulated along LDL receptor.

Contd..

Elevation of LDL in circulation leads to hypercholesterolemia and premature atherosclerosis, which develops coronary heart disease.

Familial hypercholesterolemia, patients with heterozygotes disease.

H

DL

m

etab

olis

m

Reverse cholesterol pathway

It is the process mediated by HDL, transport cholesterol from peripheral cells to liver.

Nascent HDL synthesized by intestine and liver, form discoidal HDL contain apo A1 and phospholipids (mainly lecithin).

This rapidly acquire unesterified cholesterol and additional phospholipids from peripheral tissues via transport by membrane protein ATP- binding cassette protein A1 (ABCA1).

Contd..

Defects in the gene for ABCA1 transporter lead to tangier disease (yellow tonsil, hepatomegaly) a disorder associated with low HDL and predisposition to premature coronary heart disease.

HDL cholesterol esterified by lecithin cholesterol acyl transferase (LCAT), an HDL plasma enzyme.

Contd..

HDL cholesterol is transported to hepatocytes by both an indirect and direct pathway.

HDL Cholesteryl esters are transferred to apo B containing lipoprotein in exchange for triglyceride by cholesteryl esters are then removed from circulation by LDL receptor mediated endocytosis.

CETPLCAT

Free cholesterol

hydrolysis

Reverse Cholesterol Transport: Indirect

Extrahepatic tissues

Cholesterol esters

Pre--HDL

A

HDLACholesterol to VLDL, IDL,LDL

LiverCholesterol is reusedor excreted in bile

ABCA1

Direct

Reverse Cholesterol Transport : Direct

SR-BI (scavenger receptor, class B, type 2)

Contd..

HDL cholesterol directly taken up by hepatocytes via scavenger class B1 (SR-B1), a cell surface receptor that mediates the selective transfer of lipids to cells.

Besides promoting efflux of excess cellular cholesterol, it is also an anti-oxidant, anti- inflammatory and anti-clotting properties role in reducing atherosclerosis.

Cholesterol and lipid transport by lipoproteins

Summary

Lipoprotein transport lipid in aqueous blood plasma forming non-polar lipid core (TAG + cholesteryl ester) and surrounded by single layer of amphiphatic phospholipids and cholesterol molecules.

Apolipoprotein constitute the protein moiety of lipoprotein. They act as enzyme activators (e.g. apo CII and A I) (or) ligands for cell receptors ( e.g.-apo A I, apo E, and apo B100)

4 major lipoprotein transport as follows:

chylomicrons- lipid from digestion and absorption.

VLDL- TGL from liverLDL- deliver cholesterol liver.HDL- remove cholesterol from tissues. reverse cholesterol transport.

Contd..

Absorption of lipids by intestinal mucosal cells by forming micelles where lipids are degraded by pancreatic lipase to FFA, free cholesterol and 2 MAG.

Exogenous pathway transport dietary lipids from intestine to liver ad peripheral cells, mediated by chylomicrons.

Contd..

Endogenous pathway transfer TGL to peripheral cells mediated by apolipoprotein B100.

Reverse cholesterol pathway transport cholesterol from peripheral cells to liver, mediated by HDL.

Intracellular cholesterol transport pathway is regulated by LDL-receptor and HMG-co A reducatase of cholesterol synthesis.

Contd..

Lipogenesis is regulated by acetyl coA carboxylase. Citrate activates the enzyme and long chain acyl coA inhibits.

Insulin activates acetyl coA carboxylase in the short term by dephosphorylation and in the long term by induction of synthesis.

Glucagon and epinephrine have opposite actions to insulin.

References

Clinical chemistry – Tietz, Bishop fody, martin crook.

Clinical endocrinology and diabetes mellitus by y.sachdev.

Disorder of lipoprotein metabolism- Harrison's by Larry Jameson.

Biochemistry- Harper(25thedition) and Pamela c.champe, Richard A. Harrey.