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Fatty acid metabolism begins with digestion and absorption of dietary lipids, followed by transport, oxidation, and energy production.
Dietary fats are mainly:
Triacylglycerols (TAG)
Phospholipids
Cholesterol esters
Fat-soluble vitamins
They are hydrophobic, so digestion requires emulsification.
Performed by bile salts from the liver.
Functions:
Break large fat droplets into small micelles
Increase surface area for enzymes
Keep lipids suspended in watery environment
No major digestion occurs in stomach except gastric lipase, which is minor.
Acts on TAG → 2-monoacylglycerol + free fatty acids
Requires colipase for activation
Inhibited by bile salts unless colipase binds
Converts phospholipids → lysophospholipids + fatty acid
Converts cholesterol esters → free cholesterol + fatty acid
Micelles contain:
2-monoacylglycerol
Free fatty acids
Lysophospholipids
Cholesterol
Bile salts
Micelles deliver lipids to enterocytes (brush border).
Micelles fuse with the brush border
Lipids enter by diffusion
Bile salts remain in lumen → later reabsorbed in ileum (enterohepatic circulation)
Inside the cell:
FA + CoA → Fatty acyl-CoA
2-monoglycerol + fatty acyl-CoA → TAG
Lysophospholipids → phospholipids
Cholesterol → cholesterol esters
TAG + cholesterol + phospholipids + apoB-48 → Chylomicrons
Enter:
Lymphatics (lacteals) → thoracic duct → systemic circulation
β-oxidation is the mitochondrial pathway that breaks down fatty acids to produce:
Acetyl-CoA
NADH
FADH₂
These products enter TCA cycle and electron transport chain.
Before entering mitochondria:
Fatty acid + CoA → Fatty acyl-CoA
Enzyme: Acyl-CoA synthetase
Occurs in cytosol
Requires ATP → AMP + PPi (equivalent to 2 ATP)
Long-chain fatty acids require transport.
Located on outer mitochondrial membrane
Converts fatty acyl-CoA → acyl-carnitine
Moves acyl-carnitine into matrix
Regenerates fatty acyl-CoA inside mitochondria
Inhibition:
CPT-I inhibited by malonyl-CoA (key control step)
Each cycle removes 2 carbons from the fatty acid.
Fatty acyl-CoA → trans-Δ²-enoyl-CoA
Produces FADH₂
Enoyl-CoA → Hydroxyacyl-CoA
Hydroxyacyl-CoA → Ketoacyl-CoA
Produces NADH
Ketoacyl-CoA →
Acetyl-CoA
Fatty acyl-CoA (shorter by 2C)
Cycle repeats until all carbons are released as acetyl-CoA.
Example: Palmitic acid (16C)
7 cycles of β-oxidation
8 Acetyl-CoA
7 NADH
7 FADH₂
Total ATP ≈ 106 ATP per palmitate.
(Without memorizing the number, understand pattern: more carbons → more ATP.)
Prevents simultaneous:
FA synthesis
FA oxidation
Needed for oxidation steps.
Insulin ↓ β-oxidation
Glucagon ↑ β-oxidation
Muscle weakness
Hypoglycemia
Increased long-chain fatty acids in blood
Occurs in:
Malnutrition
Liver disease
Hemodialysis
Genetic transporter defects
Muscle pain on exercise
Myoglobinuria
Rhabdomyolysis
FA oxidation blocked.
Hypoketotic hypoglycemia
Vomiting
Lethargy
Sudden infant death (SIDS association)
Occurs after fasting.
Defect in α-oxidation
Phytanic acid accumulation
Retinitis pigmentosa, neuropathy
(Important when discussing special FA pathways)
The energy yield depends on the number of carbons in the fatty acid.
It undergoes 7 cycles of β-oxidation.
7 FADH₂
7 NADH
8 Acetyl-CoA
Each FADH₂ → 1.5 ATP → 7 × 1.5 = 10.5 ATP
Each NADH → 2.5 ATP → 7 × 2.5 = 17.5 ATP
Each Acetyl-CoA → 10 ATP in TCA → 8 × 10 = 80 ATP
Minus 2 ATP used during activation → Net = 106 ATP
(This is the value usually quoted in exams.)
For a saturated fatty acid with n carbons:
Number of cycles = (n/2) − 1
Number of Acetyl-CoA = n/2
Total ATP = [ (Number of cycles × 4 ATP) + (Number of Acetyl-CoA × 10 ATP ) ] − 2
(Using modern ATP values)
Odd-chain fatty acids are found mainly in:
Dairy fats
Ruminant animals
Some plant fats
β-oxidation proceeds normally until the last cycle.
Multiple Acetyl-CoA (2-carbon units)
One Propionyl-CoA (3-carbon unit)
Propionyl-CoA → Methylmalonyl-CoA
Enzyme: Propionyl-CoA carboxylase
Requires Biotin
Methylmalonyl-CoA → Succinyl-CoA
Enzyme: Methylmalonyl-CoA mutase
Requires Vitamin B₁₂ (cobalamin)
Succinyl-CoA enters TCA cycle
Vitamin B₁₂ deficiency → methylmalonic acidemia, methylmalonic aciduria
Causes neurological damage
α-oxidation occurs when β-oxidation cannot proceed due to a methyl group at the β-carbon.
Phytanic acid (branched-chain fatty acid from dairy products)
A methyl group at β-carbon blocks dehydrogenation.
Hydroxylation at the α-carbon
Removal of 1 carbon → forms pristanic acid
Pristanic acid enters β-oxidation
Occurs mainly in peroxisomes.
Defect in phytanoyl-CoA α-hydroxylase
Leads to accumulation of phytanic acid
Retinitis pigmentosa
Peripheral neuropathy
Ataxia
Hearing loss
Avoid dairy + chlorophyll-rich foods
Plasmapheresis in severe cases
ω-oxidation occurs when β-oxidation is impaired or overloaded.
Endoplasmic reticulum (mostly liver & kidney)
Oxidation begins at the ω-carbon (terminal carbon)
Produces dicarboxylic acids
These dicarboxylic acids can undergo β-oxidation in peroxisomes
When β-oxidation is defective (e.g., MCAD deficiency), the body increases ω-oxidation.
Dicarboxylic acids appear in urine → important diagnostic clue.
β-Oxidation: mitochondrial, produces Acetyl-CoA, NADH, FADH₂
Odd-Chain FA: produce Propionyl-CoA → Succinyl-CoA (requires B₁₂)
α-Oxidation: handles branched-chain fatty acids (phytanic acid)
ω-Oxidation: ER pathway → produces dicarboxylic acids, active when β-oxidation is blocked
Organic acidurias are inborn errors of metabolism involving defects in the breakdown of amino acids and odd-chain fatty acids.
They result in the accumulation of organic acids in blood and urine → metabolic acidosis, ketosis, hypoglycemia, and neurological dysfunction.
These disorders often present in early infancy with serious symptoms after feeds.
Deficiency of methylmalonyl-CoA mutase
Or deficiency of Vitamin B₁₂
Propionyl-CoA → methylmalonyl-CoA → (blocked) → succinyl-CoA
Methylmalonic acid accumulates.
Severe metabolic acidosis
Ketosis
Hyperammonemia
Lethargy, hypotonia
Developmental delay
B₁₂ deficiency in infants mimics MMA.
Deficiency of propionyl-CoA carboxylase
Propionic acid
Methylcitrate
Recurrent vomiting
Metabolic acidosis
Hyperammonemia
Neutropenia
Low-protein diet
Biotin supplementation
Includes:
Holocarboxylase synthetase deficiency
Biotinidase deficiency
Biotin cannot be used → impaired carboxylation reactions.
Dermatitis
Alopecia
Acidosis
Seizures
Biotin supplementation dramatically improves symptoms.
Occurs mainly in:
Liver
Lactating mammary gland
Adipose tissue
Occurs in the cytosol.
Acetyl-CoA
Obtained from mitochondria but transported as citrate (citrate shuttle)
Rate-limiting enzyme
Requires biotin
Reaction: Acetyl-CoA + CO₂ → Malonyl-CoA
Activated by: Insulin, citrate
Inhibited by: Glucagon, epinephrine, AMP-activated protein kinase, palmitoyl-CoA
A large multi-enzyme protein.
Sequentially adds 2-carbon units from malonyl-CoA
Produces palmitate (16C) as primary end product
NADPH
(from HMP shunt and malic enzyme)
Each cycle includes:
Condensation
Reduction (uses NADPH)
Dehydration
Reduction (uses NADPH)
Cycle repeats until 16 carbons are reached.
Location: Cytosol
Need: Acetyl-CoA, malonyl-CoA, NADPH
Enzyme: FAS synthesizes palmitic acid (16:0)
Hormone: Insulin stimulates the entire pathway
Occurs mainly in:
Smooth endoplasmic reticulum (SER)
Mitochondria
Uses malonyl-CoA as carbon donor
Adds 2C per cycle
Produces long-chain fatty acids (>16C)
Uses acetyl-CoA as carbon donor
Mainly elongates medium-chain FA
Mechanism resembles β-oxidation in reverse (but uses NADPH)
Although not asked, this always comes with elongation in exams.
Present in ER.
Cannot introduce double bonds beyond C9
Hence linoleic and α-linolenic acids are essential fatty acids
Occurs mainly in:
Liver
Adipose tissue
Intestine
Glycerol-3-phosphate
Fatty acyl-CoA
Liver: glycerol kinase or glycolysis
Adipose tissue: only from glycolysis (due to lack of glycerol kinase)
Glycerol-3-phosphate + fatty acyl-CoA →
Lysophosphatidic acid
Addition of another fatty acid →
Phosphatidic acid
Dephosphorylation →
Diacylglycerol (DAG)
Addition of 3rd fatty acid →
Triacylglycerol (TAG)
Packaged into VLDL
Released into blood
Stored as fat droplets
Mobilized during fasting by hormone-sensitive lipase
→ Methylmalonic acidemia
→ Neurological defects
→ Recurrent acidosis, hyperammonemia
→ Excess TAG synthesis
→ Occurs in alcohol, diabetes, obesity, starvation
→ Dermatitis
→ Poor wound healing
→ Growth retardation
→ Increased ω-oxidation → dicarboxylic acids in urine
Adipose tissue is the major storage site for triglycerides (fat).
Its metabolism is controlled by insulin, glucagon, catecholamines, and overall nutritional status.
Adipocytes perform two key functions:
Lipid storage (fed state)
Lipid mobilization (fasting state)
After meals
When insulin levels are high
Dietary TAGs
Delivered as chylomicrons and VLDL.
De novo lipogenesis (from liver)
Liver converts carbohydrates → fatty acids → VLDL → adipose tissue.
Insulin stimulates LPL on capillary walls of adipose tissue.
LPL hydrolyzes TAGs in:
Chylomicrons
VLDL
→ releases free fatty acids (FFAs) + glycerol.
FFAs enter adipocytes.
Glycerol cannot be used (no glycerol kinase in adipose tissue).
Glycerol-3-P is formed from glycolysis:
Glucose → DHAP → glycerol-3-phosphate
Requires insulin because insulin ↑ glucose uptake in adipocytes.
Fatty acyl-CoA + glycerol-3-P → TAGs
TAGs are stored as lipid droplets.
Insulin promotes fat storage:
↑ LPL
↑ Glucose uptake
↑ TAG synthesis
↓ Hormone-Sensitive Lipase
↑ Lipogenesis
When fasting or during stress, adipose tissue releases fatty acids for energy.
Triggered by:
Low insulin
High glucagon
Catecholamines (epinephrine/noradrenaline)
The key enzyme responsible is Hormone-Sensitive Lipase (HSL).
HSL is the rate-limiting enzyme for lipolysis in adipose tissue.
HSL breaks down stored TAGs into:
Free fatty acids (FFA)
Glycerol
Process:
TAG → DAG → MAG → FA + glycerol
(HSL acts mainly on TAG and DAG)
Glucagon
Epinephrine
Norepinephrine
ACTH
Mechanism:
Hormones → ↑ cAMP → activates protein kinase A → phosphorylates HSL → HSL becomes active.
Insulin
Mechanism:
Insulin → ↓ cAMP → activates phosphodiesterase → dephosphorylates HSL → inactive.
Insulin also inhibits breakdown of TAGs by stimulating phosphoprotein phosphatase.
Released into blood
Carried by albumin
Used by:
Liver
Muscle
Heart
Fuel source during fasting.
Transported to liver
Converted to:
Glucose (via gluconeogenesis)
TAG synthesis
Main storage depot
Large single lipid droplet
Few mitochondria
Stores TAG for long-term energy
Many mitochondria
Rich blood supply
Contains uncoupling protein-1 (UCP-1)
Generates heat (non-shivering thermogenesis)
Prominent in newborns
Excess TAG accumulation in adipocytes
Insulin resistance increases due to adipokines
High HSL activity due to low insulin → ↑ lipolysis
Leads to ↑ FFAs → ↑ ketogenesis → diabetic ketoacidosis
Abnormal or absent adipose tissue
Causes insulin resistance and fatty liver
Causes impaired lipolysis
Leads to enlarged adipocytes and fasting intolerance
Insulin → storage (activates LPL, inhibits HSL)
Glucagon/epinephrine → mobilization (activate HSL via cAMP)
HSL = key enzyme for TAG breakdown
FFAs go to tissues for oxidation
Glycerol goes to liver for gluconeogenesis
The liver and adipose tissue work together to maintain energy balance, lipid homeostasis, and glucose metabolism.
They constantly exchange signals and metabolites depending on the fed or fasting state.
Think of them as two major metabolic partners regulating storage and release of fat.
Insulin ↑ glucose uptake
Glucose → glycerol-3-phosphate
FFA from chylomicrons/VLDL → TAG synthesis
Hormone-sensitive lipase inhibited → ↓ lipolysis
Glucose → acetyl-CoA → de novo FA synthesis
FA + glycerol → TAG
TAG → VLDL → exported to adipose tissue
Connection:
Adipose tissue stores the TAGs that liver produces.
Liver depends on adipose LPL (activated by insulin) for FFA uptake.
HSL activated → TAG breakdown
FFA released into blood (bound to albumin)
Glycerol sent to liver → gluconeogenesis
FFA undergo β-oxidation → acetyl-CoA → ATP
Excess acetyl-CoA → ketogenesis
Glycerol → glucose
Connection:
Adipose tissue supplies FFAs and glycerol → liver produces glucose and ketone bodies → used by muscle/brain.
When this axis is disturbed (by obesity, insulin resistance), the liver receives more FFAs than it can handle → fatty liver, hypertriglyceridemia, metabolic syndrome.
Obesity is a chronic metabolic disease with increased adipose mass and altered endocrine function of fat tissue.
Hypertrophic obesity → enlarged adipocytes (adult type)
Hyperplastic obesity → increased number of adipocytes (childhood type)
Adipose tissue secretes adipokines:
Signals satiety to hypothalamus
Obesity → leptin resistance
Result: persistent hunger + reduced energy expenditure
Anti-inflammatory
Enhances insulin sensitivity
Obesity → ↓ adiponectin → insulin resistance
Promote inflammation
Induce insulin resistance
Contribute to metabolic syndrome
Promotes insulin resistance
Insulin resistance
Type 2 diabetes mellitus
Dyslipidemia (↑ TAG, ↓ HDL)
Hypertension
Non-alcoholic fatty liver disease (NAFLD)
Atherosclerosis
Excess caloric intake
Sedentary lifestyle
Genetic predisposition
Sleep deprivation
Hypothyroidism
Medications (steroids, antipsychotics)
Energy storage
Endocrine organ
Large single droplet
Thermogenesis (via UCP-1)
Many mitochondria
Prominent in infants
Fatty liver occurs when triglycerides accumulate in hepatocytes because inflow > outflow.
Non-alcoholic fatty liver disease (NAFLD)
Alcoholic fatty liver disease
Obesity
High-fat diet
Increased lipolysis (uncontrolled diabetes, fasting)
High carbohydrate intake
Excess insulin
Fructose-rich diet
Hyperinsulinemia activates ACC and FAS → ↑ fatty acid synthesis
↓ VLDL synthesis
Choline deficiency
Protein malnutrition
NADH accumulation
Inhibits β-oxidation
Promotes fat deposition
→ TAG accumulation in hepatocytes
Fatty liver is often asymptomatic.
When severe:
Hepatomegaly
Right upper quadrant discomfort
Elevated liver enzymes (ALT > AST in NAFLD)
ALT < AST in alcoholic liver disease
Steatohepatitis (NASH)
Fibrosis
Cirrhosis
Hepatocellular carcinoma
Early fatty liver is reversible with weight loss and metabolic control.
Progression to NASH and fibrosis becomes partly irreversible.
Liver–Adipose Axis:
Fed state → adipose stores fat, liver makes VLDL
Fasted state → adipose releases FFAs, liver oxidizes them → ketones
Obesity:
Enlarged adipose tissue → releases inflammatory adipokines → insulin resistance
Fatty Liver:
Excess FFA delivery + high insulin + low FA oxidation → TAG buildup in liver
Lipotropic factors are substances that prevent fat accumulation in the liver.
They enhance export of fat as VLDL or increase oxidation of fatty acids.
Required to synthesize phosphatidylcholine (lecithin)
Lecithin is essential for VLDL formation
Without choline → ↓ VLDL → fatty liver
Source of methyl groups → needed for choline synthesis
Deficiency → impaired VLDL production → fatty liver
Participate in methyl group transfers
Help in methionine synthesis → indirectly maintain choline levels
Component of phospholipids
Supports membrane integrity and fat mobilization
Improve VLDL secretion
Prevent fat accumulation in hepatocytes
Choline deficiency → hepatic steatosis
High fructose diet ↑ lipogenesis, worsening fatty liver unless lipotropic factors are adequate
Ketone bodies are water-soluble fuels produced from excess acetyl-CoA when carbohydrate availability is low.
Acetoacetate
β-hydroxybutyrate
Acetone (volatile, exhaled; fruity breath smell)
Ketogenesis is the process of ketone body synthesis in the liver, occurring in the mitochondria of hepatocytes.
Prolonged fasting
Starvation
Low-carbohydrate intake
Uncontrolled diabetes mellitus
High FFA oxidation
→ massive production of acetyl-CoA
TCA cycle slows
Acetyl-CoA accumulates
Enzyme: HMG-CoA synthase (rate-limiting)
Enzyme: HMG-CoA lyase
β-Hydroxybutyrate (via NADH-dependent enzyme)
Acetone (spontaneous decarboxylation)
Liver produces ketone bodies but cannot use them (lacks thiophorase enzyme)
Ketolysis is the utilization of ketone bodies for energy by extra-hepatic tissues.
Brain (during starvation)
Skeletal muscle
Cardiac muscle
Renal cortex
β-hydroxybutyrate → acetoacetate
Acetoacetate + succinyl-CoA → acetoacetyl-CoA
Enzyme: Succinyl-CoA:acetoacetate transferase (thiophorase)
Acetoacetyl-CoA → 2 acetyl-CoA
Acetyl-CoA enters TCA cycle → ATP
Liver lacks thiophorase → cannot utilize ketone bodies.
Ketosis is the accumulation of ketone bodies in blood due to increased ketogenesis and/or decreased utilization.
Fasting
Starvation
Prolonged exercise
Low-carb ketogenic diets
Blood ketone levels mildly elevated; pH remains normal.
Occurs in uncontrolled Type 1 diabetes.
Low insulin → high glucagon → massive lipolysis
Huge FFA influx to liver → excessive ketogenesis
Acetone → fruity breath
Severe acidosis → Kussmaul breathing
Increased NADH → impaired gluconeogenesis
High fatty acid oxidation → acetyl-CoA accumulates
Leads to ketone overproduction
Brain shifts to ketone use after 2–3 days
Maximum ketone use at 20–30 days of starvation
Low insulin
High glucagon
High NADH/NAD⁺ (alcohol)
High fatty acid oxidation
Low carbohydrate availability
Decreased oxaloacetate (diverted for gluconeogenesis)
Insulin
High carbohydrate intake
Low fatty acid supply
Adequate oxaloacetate
High blood ketones
Metabolic acidosis
Hyperventilation (Kussmaul)
Fruity breath (acetone)
Ketones become major brain fuel (after 3 days)
HMG-CoA synthase deficiency → impaired ketogenesis
Thiophorase deficiency → tissues cannot use ketones → metabolic crisis
Lipotropic factors prevent fatty liver.
Ketone bodies: acetoacetate, β-hydroxybutyrate, acetone.
Ketogenesis occurs in liver mitochondria.
Ketolysis occurs in extra-hepatic tissues (not liver).
Ketosis = elevated ketones; DKA = dangerous acidotic state.
In the small intestine, aided by bile salts and pancreatic lipase.
They emulsify fats, increasing surface area for enzymatic breakdown.
Colipase.
Aggregates of fatty acids, 2-monoacylglycerol, cholesterol + bile salts that transport lipids to enterocytes.
In intestinal mucosal cells (enterocytes).
Apo-B48.
Insulin.
Mitochondrial breakdown of fatty acids to produce acetyl-CoA, NADH, FADH₂.
Acyl-CoA synthetase, requiring ATP → AMP + PPi.
Transports long-chain fatty acyl-CoA into mitochondria.
CPT-I (Carnitine Palmitoyl Transferase I).
Oxidation → hydration → oxidation → thiolysis.
Low insulin → ↑ lipolysis → ↑ acetyl-CoA → limited OAA → acetyl-CoA diverted to ketogenesis.
Acetoacetate, β-hydroxybutyrate, acetone.
It lacks thiophorase (SCOT enzyme).
HMG-CoA synthase.
Acetone.
106 ATP (net).
Propionyl-CoA (3C).
Vitamin B₁₂.
Organic aciduria due to B₁₂ deficiency or methylmalonyl-CoA mutase defect.
Oxidation in peroxisomes used for branched-chain fatty acids like phytanic acid.
Refsum disease.
ER-based oxidation at the terminal carbon, producing dicarboxylic acids.
When β-oxidation is defective (e.g., MCAD deficiency).
Acetyl-CoA, transported out of mitochondria as citrate.
Acetyl-CoA carboxylase (ACC).
Biotin.
Activated by insulin, citrate
Inhibited by glucagon, epinephrine, AMP-kinase
Palmitate (16-carbon saturated FA).
NADPH, mainly from the HMP shunt and malic enzyme.
ER and mitochondria.
Glycerol-3-phosphate + fatty acyl-CoA.
It lacks glycerol kinase.
Hormone-sensitive lipase (HSL).
Glucagon, epinephrine, via ↑ cAMP and PKA.
Insulin.
A metabolic partnership where adipose provides FFAs & glycerol to liver during fasting, and liver provides VLDL & glucose in fed state.
Signaling molecules from adipose tissue (e.g., leptin, adiponectin, TNF-α).
Leptin levels ↑ but leptin resistance develops → overeating.
Due to inflammatory adipokines: TNF-α, IL-6, resistin.
Excess triglyceride accumulation in the liver due to:
↑ FFA supply
↑ lipogenesis
↓ β-oxidation
↓ VLDL secretion
Choline (lipotropic factor).
NAFLD → insulin resistance–driven
Alcoholic → high NADH inhibits β-oxidation
Severe metabolic acidosis from unchecked ketogenesis.
High NADH/NAD⁺ ratio favors its formation over acetoacetate.
Because insulin is low but not completely absent like in DKA.
Brain (after 2–3 days fasting), heart, skeletal muscle.
Help export fat from liver → prevent fatty liver.
Converted back to acetyl-CoA → enters TCA → ATP production.
A 6-month-old infant presents with vomiting, seizures, and lethargy after a night of sleep.
Blood tests show no ketone bodies, severe hypoglycemia, and dicarboxylic acids in urine.
MCAD deficiency (Medium-chain acyl-CoA dehydrogenase deficiency)
β-oxidation fails → low acetyl-CoA → low ketones → ↑ ω-oxidation → dicarboxylic acids.
A 20-year-old male experiences extreme muscle cramps and cola-colored urine after strenuous exercise.
CK levels are high. Plasma free fatty acids rise after exercise.
CPT-II deficiency
Fatty acids cannot enter mitochondria → energy crisis in muscles → rhabdomyolysis.
A 1-year-old child has hypotonia, seizures, metabolic acidosis, and very high methylmalonic acid in urine.
Methylmalonic acidemia
Vitamin B12 deficiency, or
Methylmalonyl-CoA mutase defect
Propionyl-CoA cannot → Succinyl-CoA.
A 38-year-old diabetic man stops insulin for 2 days.
He arrives with abdominal pain, dehydration, and Kussmaul breathing. Breath smells fruity.
Diabetic ketoacidosis (DKA)
Excess lipolysis → ↑ FFAs
High acetyl-CoA → massive ketogenesis
High NADH → ↑ β-hydroxybutyrate
Metabolic acidosis
A chronic alcoholic presents with abdominal pain, tachycardia, and severe acidosis.
Blood glucose is low or normal. Ketone levels are elevated.
Alcoholic ketoacidosis
Ethanol metabolism → ↑ NADH → ↓ gluconeogenesis → ↑ lipolysis → ketone production.
A 4-year-old child presents with enlarged liver.
No hypoglycemia.
Diet history reveals high intake of polished rice + low-protein diet.
Fatty liver due to choline deficiency
↓ VLDL synthesis → fat trapped in hepatocytes
(lack of lipotropic factors: choline, methionine).
A woman consuming huge amounts of dairy products develops neuropathy, retinitis pigmentosa, and scaly skin.
Refsum disease (α-oxidation defect)
Defective phytanoyl-CoA α-hydroxylase → phytanic acid accumulation.
A 45-year-old obese man has central obesity, low HDL, high LDL, high fasting glucose.
Metabolic syndrome
Inflammatory adipokines (TNF-α, IL-6, resistin) → insulin resistance
Visceral fat → continuous FFA delivery to liver → TAG & VLDL elevation.
A 50-year-old non-drinker shows hepatomegaly, elevated ALT > AST, and ultrasound shows steatosis.
Non-alcoholic fatty liver disease (NAFLD)
Insulin resistance → ↑ lipolysis → ↑ FFA
↑ de novo lipogenesis
↓ β-oxidation
↓ VLDL export
A 3-month-old infant becomes unresponsive after 6 hours without feeding.
Blood glucose is very low and ketone bodies are also low.
CPT-I deficiency
Impaired transport of fatty acyl-CoA into mitochondria → no β-oxidation → no ketones → severe hypoglycemia.
A man fasting for 5 days has mild metabolic acidosis, ketonuria, but is alert and stable.
Physiological starvation ketosis
Low insulin → moderate ketogenesis
Brain begins using ketones → glucose sparing.
A 30-year-old drinks heavily for 12 hours.
He has vomiting, high NADH levels, and fatty liver.
Alcohol-induced fatty liver
High NADH inhibits:
β-oxidation
TCA cycle
Causing acetyl-CoA → TAG accumulation.
A 12-year-old child shows extreme leanness, liver steatosis, and high insulin levels.
Lipodystrophy
Loss of adipose tissue →
Glucose stored in liver → fat deposited in liver → insulin resistance.
A man develops severe fatigue 30 minutes after a fatty meal.
Plasma long-chain acyl-carnitine levels are high.
Carnitine deficiency
Fat cannot enter mitochondria → energy deficit.
A baby has bulky, foul-smelling stools.
History shows pancreatic insufficiency.
Impaired fat digestion due to ↓ pancreatic lipase.
Ketonuria (+3)
Serum bicarbonate normal
No dehydration
Diet-induced physiological ketosis
Not dangerous — simply low carb intake → ↑ ketogenesis.
Glucose normal
Ketone bodies normal
Lactate high
Free fatty acids ↑
Ammonia normal
β-oxidation defect (likely VLCAD or LCHAD deficiency)
Vomiting + hepatomegaly
Positive reducing sugar
No glucose in urine
Early cataracts
Galactokinase deficiency
(Overlaps FA metabolism because cataract comes from galactitol via polyol pathway)
A. CPT-I
B. Acyl-CoA synthetase
C. Hormone-sensitive lipase
D. Fatty acid synthase
Answer: B
Explanation: Activates fatty acids to fatty acyl-CoA in cytosol.
A. Short-chain fatty acids
B. Medium-chain fatty acids
C. Long-chain fatty acids
D. Ketone bodies
Answer: C
Explanation: Long-chain fatty acids cannot cross mitochondrial membrane without carnitine.
A. Insulin
B. Glucagon
C. Malonyl-CoA
D. Citrate
Answer: C
Explanation: Malonyl-CoA prevents β-oxidation during fatty acid synthesis.
A. Acetyl-CoA
B. Propionyl-CoA
C. Succinyl-CoA
D. Malonyl-CoA
Answer: B
Explanation: Final 3-carbon fragment is propionyl-CoA.
A. Vitamin B6
B. Vitamin B12
C. Biotin
D. Thiamine
Answer: B
Explanation: Methylmalonyl-CoA mutase needs vitamin B12.
A. MCAD deficiency
B. Refsum disease
C. Tay-Sachs disease
D. Gaucher disease
Answer: B
Explanation: Accumulation of phytanic acid due to α-oxidation defect.
A. Cytosol
B. Mitochondria
C. Endoplasmic reticulum
D. Peroxisomes
Answer: C
Explanation: Produces dicarboxylic acids when β-oxidation is impaired.
A. Fatty acid synthase
B. Acetyl-CoA carboxylase
C. HMG-CoA synthase
D. Glycogen phosphorylase
Answer: B
Explanation: ACC forms malonyl-CoA.
A. Stearic acid
B. Oleic acid
C. Palmitic acid
D. Arachidonic acid
Answer: C
Explanation: De novo synthesis yields palmitate (16:0).
A. Biotin
B. Thiamine
C. Choline
D. Niacin
Answer: C
Explanation: Needed for phosphatidylcholine → VLDL formation.
A. Glucose
B. Ketone bodies
C. Fatty acids
D. Lactate
Answer: B
Explanation: Brain uses ketones after 2–3 days of fasting.
A. HMG-CoA synthase
B. CPT-I
C. Thiophorase
D. Acetyl-CoA carboxylase
Answer: A
A. HMG-CoA synthase
B. Thiophorase
C. CPT-II
D. Acyl-CoA dehydrogenase
Answer: B
A. Acetoacetate
B. β-hydroxybutyrate
C. Acetone
D. Ethanol
Answer: C
A. Low NADH
B. High NADH
C. Low acetyl-CoA
D. Low fatty acid oxidation
Answer: B
A. LPL
B. HSL
C. CPT-II
D. Acetyl-CoA carboxylase
Answer: B
A. Glucagon
B. Epinephrine
C. Insulin
D. Cortisol
Answer: C
A. Increased β-oxidation
B. Increased ω-oxidation
C. Decreased lipogenesis
D. Increased esterification
Answer: B
A. High ketones
B. Normal fatty acid oxidation
C. Hypoketotic hypoglycemia
D. Hyperketosis
Answer: C
A. Glycolysis
B. HMP shunt
C. TCA cycle
D. Mitochondrial ETC
Answer: B
A. Activates HSL
B. Activates LPL
C. Inhibits glycolysis
D. Inhibits TAG formation
Answer: B
A. CPT-I
B. Uncoupling protein-1
C. Carnitine
D. FAS complex
Answer: B
A. Lack of lipoproteins
B. High NADH inhibiting β-oxidation
C. Excess dietary fat
D. Elevated insulin
Answer: B
A. Insulin
B. Glucagon
C. TSH
D. Aldosterone
Answer: B
A. Glycerol kinase
B. Glycolysis
C. Pentose phosphate pathway
D. Amino acid breakdown
Answer: B
Explanation: Adipose lacks glycerol kinase; depends on glucose supply.
Small intestine, aided by bile salts and pancreatic lipase.
They emulsify fats, increasing surface area for lipase action.
Pancreatic lipase, with the help of colipase.
Aggregates of fatty acids, 2-monoacylglycerol, cholesterol + bile salts used for absorption.
In intestinal mucosal cells (enterocytes).
Hydrolyzes TAGs in chylomicrons & VLDL into FFAs for uptake into tissues.
Insulin.
Mitochondrial breakdown of fatty acids into acetyl-CoA, NADH, FADH₂.
In the cytosol, via acyl-CoA synthetase.
It transports long-chain fatty acyl-CoA into mitochondria.
CPT-I.
Two carbons as acetyl-CoA.
106 ATP.
Propionyl-CoA.
Vitamin B₁₂.
Oxidation of branched-chain fatty acids (e.g., phytanic acid) in peroxisomes.
Refsum disease.
Oxidation at the terminal carbon of a fatty acid; occurs in the endoplasmic reticulum, forming dicarboxylic acids.
When β-oxidation is defective (e.g., MCAD deficiency).
Acetyl-CoA carboxylase (ACC).
Biotin.
Acetyl-CoA, transported out of mitochondria as citrate.
Palmitate (16-carbon saturated fatty acid).
HMP shunt and malic enzyme.
It lacks glycerol kinase.
Hormone-sensitive lipase (HSL).
Insulin.
Glucagon, epinephrine, norepinephrine, via ↑ cAMP.
A metabolic partnership where:
Liver sends VLDL & glucose to adipose tissue
Adipose sends FFAs & glycerol to liver
Because adipose tissue releases inflammatory adipokines (TNF-α, IL-6, resistin).
Leptin → due to leptin resistance.
↑ FFA delivery to liver
↑ de novo lipogenesis
↓ β-oxidation
↓ VLDL secretion
Choline (lipotropic factor).
Acetoacetate, β-hydroxybutyrate, acetone.
In mitochondria of liver.
It lacks thiophorase (SCOT).
HMG-CoA synthase.
Acetone.
Because insulin is low but not absent, so ketone production is controlled.
High ketones + metabolic acidosis + high NADH/NAD⁺ → ↑ β-hydroxybutyrate.
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