Lipid Metabolism - Flashcards (Video Notes)

A set of Q&A flashcards covering fatty acid synthesis, ketogenesis, cholesterol and bile acid metabolism, lipoproteins, regulation, and related disorders and therapies.

What is the fatty acid synthase complex structurally?

A dimer of two identical polypeptide subunits, comprising six enzymes and one acyl carrier protein (ACP).

In which tissues is fatty acid synthesis predominantly active?

Liver, lactating mammary gland, adipocytes, kidney and brain.

List the enzymes in fatty acid synthase in order from KS to TE.

Ketoacyl synthase (KS) → Transacylase (AT) → Dehydratase (DH) → Enoyl reductase (ER) → Ketoacyl reductase (KR) → Thioesterase (TE); ACP accompanies as carrier.

What residue of one FA synthase subunit lies near what moiety on the other subunit?

Cysteine-SH of one subunit lies close to the phosphopantetheine-SH of the other.

What substrates are required for fatty acid synthesis?

NADPH, acetyl CoA and bicarbonate.

Which enzyme carboxylates acetyl CoA to malonyl CoA?

Acetyl CoA carboxylase (biotin as a cofactor).

Which enzyme forms acetyl ACP from acetyl CoA?

Acetyl transacylase.

Which enzyme forms malonyl ACP from malonyl CoA?

Malonyl transacylase.

What is formed when malonyl ACP condenses with acetyl CoA?

Acetoacetyl ACP (catalyzed by ketoacyl synthase).

What is the first beta-ketoacyl product formed in FA synthesis?

Acetoacetyl ACP.

Which enzyme reduces acetoacetyl ACP to beta-hydroxybutyryl ACP?

Ketoacyl reductase (KR).

Which enzyme dehydrates beta-hydroxybutyryl ACP to crotonyl ACP?

Dehydratase (DH).

Which enzyme reduces crotonyl ACP to butyryl ACP?

Enoyl reductase (ER). NADPH used.

How many cycles are needed after butyryl ACP to form palmitoyl ACP?

Six more cycles (to reach 16 carbons, palmitoyl ACP).

Which enzyme hydrolyzes palmitoyl ACP to palmitic acid?

Thioesterase.

What is the rate-limiting enzyme of de novo fatty acid synthesis?

Acetyl CoA carboxylase.

Which cofactor provides the reducing power for FA synthesis?

NADPH.

What gene arrangement ensures coordinated synthesis of all FA synthase enzymes?

A single gene coding for the multi-enzyme polypeptide complex.

How is cytosolic acetyl CoA supplied for FA synthesis?

Export of citrate from mitochondria and cleavage by citrate lyase; acetyl CoA transported via carnitine shuttle.

What are the two primary sources of cytosolic NADPH for FA synthesis?

HMP shunt (pentose phosphate pathway) and malic enzyme pathway.

What stimuli promote fatty acid synthesis?

Citrate; increased ATP (citrate buildup); high carbohydrate diet; insulin (activates ACC and citrate lyase synthesis).

Name inhibitors of acetyl CoA carboxylase mentioned in the notes.

Palmitoyl CoA inhibits ACC; cyclic AMP (via phosphorylation) inhibits ACC; starvation/diabetes/ high fat diet inhibit FA synthesis by inhibiting ACC.

How does fatty acid synthesis differ from beta-oxidation in tissue localization?

Synthesis: liver and adipose tissue; Beta-oxidation: heart, muscle, liver.

What is the end product of de novo FA synthesis?

Palmitate (palmitoyl CoA).

What intermediates are bound to ACP versus CoA in FA metabolism?

FA synthesis uses acyl carrier protein (ACP); beta-oxidation uses CoA-bound intermediates.

Which coenzyme is required for FA synthesis and which coenzymes are used elsewhere?

NADPH is required for FA synthesis; FAD and NAD are used in beta-oxidation.

What is the primary transport system for acetyl CoA to the cytosol?

Citrate shuttle (citrate exported from mitochondria to cytosol and cleaved to acetyl CoA).

What is the key transport system for fatty acid entry into mitochondria for oxidation?

Carnitine shuttle.

What are the two key rate-limiting enzymes compared in FA synthesis vs beta-oxidation?

Acetyl CoA carboxylase (FA synthesis) vs Carnitine palmitoyl transferase I (CPT I) (beta-oxidation).

What inhibits CPT I and why is it important for regulation?

Malonyl CoA inhibits CPT I, preventing simultaneous fatty acid synthesis and oxidation.

What is a primary hormonal status that favors fatty acid synthesis?

High insulin to glucagon ratio.

What is the role of GLUT4 in FA metabolism and its hormonal control?

GLUT4 is insulin-dependent and is inhibited in insulin deficiency, reducing glucose uptake for FA synthesis in muscle and adipose.

Define ketone bodies.

Acetone, acetoacetate, and beta-hydroxybutyrate; water-soluble and energy-yielding.

Where is ketone body synthesis (ketogenesis) occurring?

Liver, in the mitochondrial matrix.

What is the rate-limiting enzyme of ketone body synthesis?

HMG CoA synthase.

Which tissues can utilize ketone bodies?

Extrahepatic tissues (skeletal muscle, cardiac muscle, kidney); brain during prolonged starvation; erythrocytes cannot due to lack of mitochondria.

Why can't the liver utilize ketone bodies?

Liver lacks thiophorase (succinyl-CoA: acetoacetate transferase).

What is the rate-limiting enzyme of ketone body utilization (ketolysis)?

Thiophorase.

What stimulates ketogenesis?

Glucagon and low insulin stimulate ketogenesis (and reduce glycolysis); starvation increases beta-oxidation and acetyl CoA supply.

What inhibits ketogenesis?

Insulin inhibits ketogenesis (stimulates glycolysis).

Name the ketogenic vs anti-ketogenic substances.

Ketogenic: fatty acids and certain ketogenic amino acids; Anti-ketogenic: glucose, glycerol, and glucogenic amino acids.

What tests detect ketone bodies in urine and how are results interpreted?

Rothera’s test (positive for acetone/acetoacetate); Ketostix detect acetoacetate; Benedict’s test can help differentiate ketosis in some contexts.

How is diabetic ketoacidosis detected vs starvation ketosis using Benedict’s and Rothera’s tests?

Diabetic ketoacidosis: Benedict’s and Rothera’s positive; starvation ketosis: Benedict’s negative, Rothera’s positive.

How is ketoacidosis treated?

Administer insulin and glucose, give bicarbonate if needed, and maintain fluids and electrolyte balance.

What is the fate of free fatty acids after lipolysis and activation?

Adipose lipolysis releases FFA; FFAs activate to acyl-CoA in liver and other tissues for oxidation or reesterification.

What enzyme activates free fatty acids to acyl CoA?

Acyl-CoA synthetase (thiokinase).

What is the rate-limiting enzyme of cholesterol synthesis?

HMG CoA reductase.

Where does cholesterol synthesis primarily occur?

In all tissues, with liver as the major site; involves cytosolic formation of HMG CoA and ER steps.

What is the initial step and subsequent key steps of cholesterol synthesis called?

Acetyl CoA → acetoacetyl CoA (thiolase) → HMG CoA (HMG CoA synthase) → mevalonate (HMG CoA reductase) → isoprenoid units → squalene → lanosterol → 7-dehydrocholesterol → cholesterol.

What regulates HMG CoA reductase activity?

Active when dephosphorylated; inhibited when phosphorylated. Insulin and thyroxine promote activation; glucagon/cAMP and glucocorticoids promote inactivation.

What enzyme is the rate-limiting step in bile acid synthesis?

7 alpha-hydroxylase.

What are primary bile acids?

Cholyl CoA (to cholic acid) and chenodeoxycholyl CoA (to chenodeoxycholic acid).

What are bile salts and how are they formed?

Primary bile acids conjugated with glycine or taurine to form bile salts (e.g., glycocholate, taurocholate).

What are secondary bile acids and give examples?

Bacterial modification in the intestine; examples include deoxycholic acid and lithocholic acid.

What is ursodeoxycholic acid?

A tertiary bile acid formed in liver by epimerization of lithocholic acid.

From cholesterol, which steroid hormones are synthesized?

Glucocorticoids, mineralocorticoids, progestins, androgens, estrogens.

What is calcitriol and where is it formed?

Calcitriol is the active form of vitamin D; formed in kidney by 1 alpha hydroxylase (from 25-hydroxycholecalciferol).

What is the rate-limiting enzyme in calcitriol synthesis?

1 alpha hydroxylase.

What is hypercholesterolemia and name four common causes listed?

Elevated blood cholesterol; causes include diabetes mellitus, hypothyroidism, obstructive jaundice, nephrotic syndrome.

Name a familial chylomicronemia type I feature and cause.

Type I: Lipoprotein lipase deficiency; eruptive xanthomas, abdominal pain, pancreatitis; severe hypertriglyceridemia.

Name a familial hypercholesterolemia type IIa feature and cause.

Type IIa: LDL receptor deficiency; tendon xanthomas; high LDL.

What is Tangier disease and its genetic basis?

Tangier disease is due to ABCA1 transporter mutation leading to severe HDL deficiency and orange tonsils.

What is abetalipoproteinemia?

Impaired apo B secretion; fat malabsorption; low LDL; fat-soluble vitamin deficiency; neurologic signs.

What are the main lipoproteins and their densities (from lowest to highest density)?

Chylomicrons (lowest density) → VLDL → LDL → HDL (highest density).