This document summarizes key aspects of lipid metabolism, including digestion and absorption of lipids, the fate of absorbed lipids, mobilization of fatty acids from adipose tissue, beta-oxidation of fatty acids, ketone body formation and utilization, lipogenesis, and the clinical importance of lipid metabolism. Key points covered include the roles of bile acids and pancreatic lipases in lipid digestion, the formation and function of chylomicrons, hormone-sensitive lipase activation of fatty acid mobilization, fatty acid activation and beta-oxidation pathways, ketogenesis in the liver, the steps and regulation of lipogenesis, and clinical correlates such as ketoacidosis and fatty acid oxidation defects.

1. LIPID METABOLISM
Level 200
BY
OHENEBA HAGAN

2. OBJECTIVES
• LIPID DIGESTION AND ABSORPTION ESPECIALLY TRIACYLGLYCEROL
• FATE OF ABSORBED LIPID
• FREE FATTY ACID MOBILISATION FROM ADIPOSE TISSUE
• b-OXIDATION OF STAIGHT CHAIN SATURATED FATTY ACIDS
• OTHER FORMS OF DEGRADATION OF FATTY ACIDS (UNSATURATED, BRANCHED
CHAIN, a-OXIDATION, W-OXIDATION)
• KETONE BODY FORMATION, UTILIZATION AND SIGNIFICANCE
• LIPOGENESIS
• CLINICAL IMPORTANCE OF LIPID METABOLISM

3. Digestion and Absorption
Dietary Lipids
TAG 90%
Cholesterol
Cholesterol Esters
Phospholipids

4. Lipid Digestion
Acid stable lingual and gastric lipases. SCFA (<12C) eg in milk
Problem of lipids- hydrophobic and enzymes work in hydrophilic environment
Bile acids produced in liver and stored in gall bladder
Forms amphipathic micelles in small intestine with fat globules
Pancreatic lipases enter micelles and digest lipids

5. • Triglycerides (TG)
TG + H2O → Diglyceride + fatty acid (FA)
Diglyceride + H2O → Monoglyceride (MG) + FA
• Cholesterol esters & phospholipids (PL)
↓ esterase ↓ phospholipases
FA + cholesterol (chol) FA + lyso PL

6. Micelles containing the FFA, Monoacylglycerol, cholesterol and lysophospholipids are presented
to the duodenal and jejunal enterocytes for absorption

7. Chylomicron

8. Clinical Correlation
The drug Orlistat for weight loss inhibits pancreatic
lipase leading reduced TAG malabsorption and
weight loss.
Malabsorption of lipids (steatorrhoea)
Results
From bile acid insufficiency eg liver disease,
gastrointestinal resection.
Pancreatic insufficiency eg pancreatitis

9. Fate of absorbed lipids
The chylomicron enters the blood stream via the lymphatic system.
The APO C-II binds to the capillary endothelial lipoprotein lipase.
Lipoprotein lipase then hydrolyses the TAG to Free Fatty Acids (hydrophobic)
FFA then bind to albumin for transport target organs like skeletal and cardiac muscles
FFA in the cells are either oxidised for energy, re-esterified back to TAG in adipose
tissue for storage
Glycerol
Moves to the liver, phosporylated to glycerol phosphate which can enter the
gluconeogetic or the glycolysis pathways
Can be re-esterified with fatty acids to TAG

10. Chylomicron remnant (after action of
lipoprotein lipase) made up of TAG, cholesterol
esters, free cholesterol, phospholipids move to
the liver.
TAGs oxidised for energy or for ketone body
formation

11. Mobilization of Fatty Acids from
Adipose Tissues
Hormone dependent
Receptors activated by hormones
(glucagon, epinephrine)
cAMP from activated receptor activates
Protein Kinase
PKA then activates Hormone Sensitive
Lipase (HSL)
PKA phosphorylates perilipin (blocks access
to fat globules when not phosphorylated)
HSL then hydrolyses TAGs in adipose
storage to release FFA
FFA then enters blood stream
Transported to tissues eg myocytes bound
to albumin

12. Fatty Acid Oxidation
Fatty Acid Activation
Before fatty acid can be catabolized, it needs to be activated first

13. Carnitine
Source: Mainly through diet. De novo synthesis from lysine and methionine
Deficiency results from dietary insufficiency, increased demand (pregnancy,
trauma), haemodialysis.
Deficiency leads to toxic accumulation of LCFA in cytosol and muscle
weakness; hypoglycaemia.
Can also occur from carnitinepalmitoyl transferase (CPT1 and CPT2)
dysfunction
Treatment is oral supplementation with carnitine.
The diabetic drugs sulphonylureas (tolbutamide and glyburide) reduce
circulating blood sugar by inhibiting CPT1

14. b-oxidation of fatty acid
Straight Chain Saturated FA

15. ATP yield for FFA oxidation of Palmitic
Acid- 16C

16. Oxidation of unsaturated FA

17. Oxidation of Odd Numbered FA
Usually naturally occurring fatty acids are even numbered, however some
plants and marine animals have odd numbered FA.
Catabolism leads to 3C propionyl CoA which is carboxylated in presence of
Biotin
The succinyl CoA then enters the Kreb’s Cycle

18. Clinical significance
Medium chain acyl CoA dehydrogenase (MCAD)
deficiency (autosomal recessive, common in
Europeans). Accumulation of MCFA leading to
hypoglycaemia and neurological symptoms

19. b-oxidation of long chain fatty acids also takes
place in peroxisomes yielding H2O2 and Acetyl
CoA. H2O2 is immediately cleaved to O2 and H2O
by catalase.
In Zellweger syndrome-cells lack peroxisomes.
Accumulation of VLCFA

20. a-oxidation of branched chain FA
Eg phytanic acid from plants.
Initially hydroxylated by fatty acid a-hydroxylase
Its then carboxylated and then activated to its CoA form.
The product then undergoes b-oxidation
In rare genetic disease Refsum’s disease, the individuals lack the hydroxylase
and are thus unable to catabolise branched chain FA.
Symptoms are mainly neurological
Treatment is by dietary restriction

21. w-oxidation
Minor pathway for FA metabolism.
Takes place in endoplasmic reticulum
Becomes important when there is dysfunction of
b-oxidation pathway or the carnitine transport
system

22. Ketogenesis (ketone bodies formation)
The fate of Acetyl CoA is either the entry into the Kreb cycle or the ketogenetic
pathway
Ketogenesis leads to the production of ‘ketone bodies’ in the form of acetone,
hydroxybutyrate and acetoacetate
In diabetes and starvation when b-oxidation of fatty acids increase leading to
increased acetyl CoA.
Because of increased gluconeogenesis, there is depletion of kreb cycle intermediates
leading to shunting of Acetyl CoA into ketogenesis which primarily occurs in
mitochondria of the liver

24. Clinical correlates
In uncontrolled diabetes, lack of insulin leads to increased fatty acid oxidation to
provide fuel for tissues.
Increased Acetyl CoA leads to increased ketone bodies.
Ketone bodies (acetoacetate and hydroxybutyrate) are acidic and therefore in large
quatities will lead to metabolic acidosis (ketoacidosis)-potentially fatal if untreated
Acetone formed is volatile and exhaled as a characteristic smell to the breath
In starvation, there is depletion of kreb’s cycle intermediates for gluconeogenesis +
increased fatty acid breakdown.
This leads to increased ketone body formation for alternate source of energy.

25. Lipogenesis
Takes place in the cytosol of Liver, kidney, brain, lung, mammary gland, and adipose
tissue
Main source of substrate Acetyl CoA is from glucose metabolism especially in the fed
state
Step 1:
Formation of Malonylcoenzyme A is the committed step in fatty acid synthesis: It
takes place in two steps: carboxylation of biotin (involving ATP) and transfer of the
carboxyl to acetyl-CoA to form malonyl-CoA.

26. Lipogenesis
Step 2
Rest of the reaction is catalyzed by
multienzyme complex fatty acid synthase
First step is C-C formation between
malonyl CoA and acetyl CoA.
Product undergoes reduction, dehydration,
and further reduction
The product is further condensed with
malonyl CoA. Each elongation adds 2
carbons to the product
Product remains attached to enzyme
complex and only released by hydrolysation
when the carbon length reaches 16

27. Lipogenesis
Fate of Palmitate
Palmitate needs to be activated by addition of CoA
Elongation
Elongation beyond the 16-C length of the palmitate product of Fatty Acid Synthase is mainly
catalyzed by enzymes associated with the endoplasmic reticulum (ER).
ER enzymes lengthen fatty acids produced by Fatty Acyl Synthase as well as dietary
polyunsaturated fatty acids.
Fatty acids esterified to coenzyme A serve as substrates.
Malonyl-CoA is the donor of 2-carbon units in a reaction sequence similar to that of Fatty
Acid Synthase except that individual steps are catalyzed by separate proteins.
A family of enzymes designated Fatty Acid Elongases or ELOVL (elongation of very long
chain fatty acid) catalyze the initial condensation step.

28. Desaturation
Carried out in the smooth endoplasmic reticulum
Catalysed by mixed oxidase enzyme-desaturase
Adds C=C in cis position
Mammals are unable to have C=C at position C9 and 12-essential fatty acid needed in
diet (linoleic and linolenic acid)
Esterification
With glycerol and other FA to form TAG
With cholesterol to from cholesterol esters

29. Assignment
Cholesterol synthesis and transport
Lipoproteins