Lipoprotein, lipid transport and

Hormonal influence on lipid

metabolism

SHIVAGOVINDAN K.P
MSC, MEDICAL BIOCHEMISTRY
 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 HDL
2) 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, Modulator of hepatic uptake of VLDL and IDL
IDL, HDL (also involved in activation of LCAT)
Apo C-II Chylomicrons, VLDL, Activator of LPL
IDL, HDL
Apo C-III Chylomicrons, VLDL, Inhibitor of LPL activity
IDL, HDL
Apo E Chylomicrons, VLDL, Ligand for binding of IDL & remnants to
IDL, HDL 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.
 HORMONAL SENSITIVE
LIPASE
ATP
ATP Pi
Adenylyl cAMP
cyclase + Dependent PK Lipase Phosphatase

ADP
cAMP
TAG
Phospho HORMONAL SENSITIVE
diestrase LIPASE
FFA + DAG
5’ AMP

FFA + DAG
HORMONAL
SENSITIVE
LIPASE FFA + MAG
FFA + MAG
2 MAG LIPASE
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.
Chylomicron
metabolism
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.
VLDL metabolism
 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.
 HDL
metabolism
 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.
 Reverse Cholesterol Transport: Indirect

Extrahepatic tissues

Liver
Cholesterol esters Cholesterol is reused
or excreted in bile
hydrolysis
Direct
Free cholesterol

ABCA1
A
LCAT CETP Cholesterol to
Pre-β -HDL A HDL
VLDL, IDL,LDL
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 liver
LDL- 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.