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Biochemistry and Metabolism - Topics 4.1 to 4.7

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4.1 Dietary Lipid Metabolism: Digestion, Absorption, and Fatty Acid Biosynthesis

Digestion and Absorption of Lipids

• Cholecystokinin (CCK) from the duodenal mucosa triggers bile release from the gallbladder and pancreatic enzyme secretion. Secretin stimulates bicarbonate release.
• Bile salts emulsify dietary fat, dramatically increasing the surface area for enzyme action.
• Pancreatic lipase, aided by colipase (which restores lipase activity in the presence of bile salts), hydrolyzes TAG at positions sn-1 and sn-3, yielding 2-monoacylglycerol (2-MAG) + 2 free fatty acids.
• Cholesterol esterase hydrolyzes cholesteryl esters; phospholipase A2 acts on phospholipids.
• The products (2-MAG, FFA, cholesterol, lysolecithin) are packaged into mixed micelles with bile salts and diffuse into enterocytes.

• Inside enterocytes, TAG is resynthesized from 2-MAG and fatty acyl-CoA.
• TAG, along with cholesterol and apolipoprotein B-48 (apo B-48), is assembled into chylomicrons in the smooth endoplasmic reticulum and Golgi.
• Chylomicrons are secreted into the lymphatic system (lacteals) - NOT directly into blood - and travel via the thoracic duct to the bloodstream.
• Short- and medium-chain FA (<12C) are absorbed directly into portal blood bound to albumin.

Biosynthesis of Palmitic Acid from Acetyl-CoA

1. Acetyl-CoA transport from mitochondria: Acetyl-CoA cannot cross the inner mitochondrial membrane directly. It is condensed with oxaloacetate (OAA) to form citrate, which exits via the citrate transporter. In the cytosol, ATP-citrate lyase cleaves citrate back to acetyl-CoA and OAA. This is activated by insulin.
2. Committed step - Acetyl-CoA Carboxylase (ACC): Acetyl-CoA + CO₂ + ATP → Malonyl-CoA
   • This is the rate-limiting step, requiring biotin as a cofactor.
   • Allosteric regulation: Citrate activates; palmitoyl-CoA inhibits.
   • Hormonal regulation: Insulin activates (via dephosphorylation); epinephrine/glucagon inactivate (via AMPK-mediated phosphorylation).
3. Fatty Acid Synthase (FAS) - a multifunctional homodimer:
   • Each monomer contains 6 catalytic domains + an acyl carrier protein (ACP) domain bearing 4'-phosphopantetheine (derived from pantothenic acid, vitamin B5).
   • The cycle (repeated 7 times to make palmitate from 1 acetyl-CoA + 7 malonyl-CoA):
     • Condensation: Acetyl group + malonyl group → 4C β-ketoacyl-ACP + CO₂
     • Reduction 1 (NADPH): β-keto → β-hydroxy
     • Dehydration: β-hydroxy → trans-2-enoyl (removes H₂O, creates double bond)
     • Reduction 2 (NADPH): trans-2-enoyl → saturated acyl-ACP
   • After 7 cycles, the 16-carbon palmitoyl group is cleaved from ACP as free palmitate (16:0).

Acetyl-CoA + 7 Malonyl-CoA + 14 NADPH → Palmitate + 7 CO₂ + 14 NADP⁺ + 8 CoA + 6 H₂O

Biosynthesis of Other Fatty Acids

• Elongation: Occurs in the smooth endoplasmic reticulum (SER). Adds 2-carbon units from malonyl-CoA to the carboxyl end of palmitate or other fatty acids. Elongation of VLCFA occurs in peroxisomes.
• Desaturation: The Δ9-desaturase (stearoyl-CoA desaturase) in the SER converts stearate (18:0) → oleate (18:1, Δ9). Humans cannot insert double bonds beyond Δ9, so linoleic acid (18:2, ω-6) and α-linolenic acid (18:3, ω-3) are essential fatty acids.

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4.2 Mobilization of Stored Fats, Oxidation of Fatty Acids, and Ketone Bodies

Mobilization of Stored Fats

• Activated by epinephrine and glucagon (via cAMP → PKA → phosphorylation of HSL and perilipin)
• Inhibited by insulin
• HSL, along with adipose triglyceride lipase (ATGL) and monoglyceride lipase, sequentially hydrolyze TAG → DAG → MAG → glycerol + 3 FFA

• FFA: Transported in blood bound to albumin → taken up by liver, muscle, heart, kidneys for beta-oxidation.
• Glycerol: Transported to liver, converted to glycerol-3-phosphate for gluconeogenesis or glycolysis.

Beta-Oxidation of Fatty Acids

• Long-chain fatty acyl-CoA (LCFA-CoA) cannot cross the inner mitochondrial membrane.
• CPT-I (carnitine palmitoyltransferase-I, outer membrane) transfers the acyl group to carnitine.
• Acylcarnitine crosses via carnitine-acylcarnitine translocase.
• CPT-II (inner membrane) transfers acyl group back to CoA inside the matrix.
• Key regulation: Malonyl-CoA inhibits CPT-I, preventing simultaneous synthesis and oxidation of fatty acids.
• Carnitine is synthesized from lysine and methionine in liver/kidney. Primary carnitine deficiency (OCTN2 defect) causes impaired LCFA oxidation.

1. FAD-linked dehydrogenation (acyl-CoA dehydrogenase): Creates trans-2-enoyl-CoA + FADH₂
2. Hydration: Trans-2-enoyl-CoA + H₂O → L-3-hydroxyacyl-CoA (enoyl-CoA hydratase)
3. NAD+-linked dehydrogenation: L-3-hydroxyacyl-CoA → 3-ketoacyl-CoA + NADH (3-hydroxyacyl-CoA dehydrogenase)
4. Thiolysis: 3-ketoacyl-CoA + CoA → Acetyl-CoA + shortened acyl-CoA (thiolase)

• 7 cycles yield: 7 FADH₂ + 7 NADH + 8 Acetyl-CoA
• 8 Acetyl-CoA × 10 ATP = 80 ATP; 7 FADH₂ × 1.5 = 10.5; 7 NADH × 2.5 = 17.5
• Gross: ~108 ATP; minus 2 (activation) = ~106 ATP net

• MCAD deficiency: Medium-chain acyl-CoA dehydrogenase deficiency causes hypoketosis + severe hypoglycemia (most common FA oxidation defect)
• Odd-chain FA: Produce propionyl-CoA → methylmalonyl-CoA (propionyl-CoA carboxylase, biotin-dependent) → succinyl-CoA (methylmalonyl-CoA mutase, vitamin B12-dependent). Deficiency causes methylmalonic acidemia.
• VLCFA oxidation: Occurs in peroxisomes (not mitochondria). X-linked adrenoleukodystrophy = defect in ABCD1 transporter for VLCFA into peroxisomes.
• Branched-chain FA (e.g., phytanic acid): Require alpha-oxidation in peroxisomes (Refsum disease = phytanoyl-CoA hydroxylase deficiency).

Production and Use of Ketone Bodies

1. 2 Acetyl-CoA → Acetoacetyl-CoA (thiolase)
2. Acetoacetyl-CoA + Acetyl-CoA → HMG-CoA (HMG-CoA synthase)
3. HMG-CoA → Acetoacetate + Acetyl-CoA (HMG-CoA lyase)
4. Acetoacetate → 3-Hydroxybutyrate (β-hydroxybutyrate dehydrogenase, NADH-requiring)
5. Acetoacetate → Acetone (spontaneous decarboxylation; excreted in breath)

• 3-Hydroxybutyrate → Acetoacetate (β-hydroxybutyrate dehydrogenase)
• Acetoacetate + Succinyl-CoA → Acetoacetyl-CoA + Succinate (thiophorase = succinyl-CoA:3-ketoacid-CoA transferase)
• Acetoacetyl-CoA → 2 Acetyl-CoA → TCA cycle

• The liver lacks thiophorase, so it cannot use ketone bodies - it only produces them for peripheral tissues.
• The brain normally uses glucose but shifts to ketone bodies during prolonged starvation (after ~3-4 days) - this is why starvation does not cause immediate brain damage.
• Diabetic ketoacidosis (DKA): In uncontrolled T1DM, unopposed glucagon drives massive ketogenesis. Ketone bodies lower blood pH → metabolic acidosis. Serum shows high anion gap, positive urine ketones, hyperglycemia, ketonuria.

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4.3 Cholesterol: Structure, Biosynthesis, and Lipoprotein Metabolism

Structure and Function of Cholesterol

Cholesterol Biosynthesis

• 2 Acetyl-CoA → Acetoacetyl-CoA
• • Acetyl-CoA → HMG-CoA (HMG-CoA synthase, cytosolic isozyme)

• HMG-CoA + 2 NADPH → Mevalonate (HMG-CoA reductase)
• This step is inhibited by statins (competitive inhibitors)
• Regulation of HMG-CoA reductase:
  • Substrate-level: Sterol-mediated feedback - excess intracellular cholesterol promotes reductase degradation and reduces its transcription via SREBP2 (sterol regulatory element-binding protein 2)
  • Phosphorylation: AMPK phosphorylates and inactivates reductase; insulin-stimulated phosphatase reactivates it
  • Statins (lovastatin, atorvastatin) competitively inhibit the enzyme, reducing cholesterol synthesis and upregulating LDL receptors

• Mevalonate → Isopentenyl pyrophosphate (IPP, 5C)
• 3 IPP → Farnesyl pyrophosphate (FPP, 15C)
• 2 FPP → Squalene (30C) → Lanosterol → Cholesterol (27C)

Metabolism of Lipoproteins

• Made in intestinal mucosal cells, enter lymph, then blood
• Apo C-II (donated by HDL) activates lipoprotein lipase (LPL) on capillary endothelium → hydrolyzes TAG → FFA (for muscle/adipose) + glycerol (for liver)
• Remnant (enriched in cholesterol, apo E) is taken up by liver via LDL receptor-related protein (LRP) using apo E as ligand

• Synthesized in liver from endogenous TAG + apo B-100
• LPL degrades TAG → IDL → LDL
• CETP (cholesteryl ester transfer protein) exchanges TAG from VLDL for CE from HDL

• Apo B-100 on LDL binds the LDL receptor → receptor-mediated endocytosis → lysosomal degradation → cholesterol released intracellularly
• Excess cholesterol: inhibits HMG-CoA reductase + SREBP2; activates ACAT (esterifies cholesterol for storage)
• PCSK9 prevents LDL receptor recycling (PCSK9 inhibitors, e.g., evolocumab, increase LDL receptor density)
• Familial hypercholesterolemia (FH): Autosomal dominant defect in LDL receptor → type IIa hyperlipoproteinemia, premature atherosclerosis

• Nascent HDL (disc-shaped, apo A-I) accepts cholesterol from peripheral tissues via ABCA1 transporter
• LCAT (lecithin:cholesterol acyltransferase, activated by apo A-I) esterifies cholesterol → cholesteryl esters enter HDL core → disc becomes sphere
• Mature HDL delivers CE to liver via SR-B1 (scavenger receptor B1)
• HDL is protective (inverse relationship with cardiovascular risk)

• Type I: LPL or apo C-II deficiency → chylomicronemia (pancreatitis risk)
• Type IIa: LDL receptor defect (FH) → elevated LDL
• Type III: Apo E2/E2 → accumulation of IDL + chylomicron remnants (dysbetalipoproteinemia)

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4.4 Protein Digestion, Amino Acid Nitrogen Disposal, and the Urea Cycle

Digestion and Absorption of Proteins

• Trypsin: Cleaves after Lys, Arg
• Chymotrypsin: Cleaves after aromatic residues
• Elastase: Cleaves after small neutral AAs
• Carboxypeptidases (A and B): Exopeptidases cleaving from C-terminus

Amino Acid Nitrogen Disposal

• AST (aspartate aminotransferase): Asp + α-KG ↔ OAA + Glu
• ALT (alanine aminotransferase): Ala + α-KG ↔ Pyruvate + Glu

• Alanine-glucose cycle (muscle): NH₃ is transferred to pyruvate (via transamination) → alanine; alanine travels to liver, where ALT regenerates pyruvate + NH₃. Pyruvate → gluconeogenesis; NH₃ → urea cycle.
• Glutamine (brain, muscle): NH₃ + Glutamate → Glutamine (glutamine synthetase, ATP-dependent). Glutamine travels to liver/kidney; glutaminase regenerates glutamate + NH₃.

Urea Cycle

1. CPS-I (mitochondria): NH₃ + CO₂ + 2 ATP → Carbamoyl phosphate (uses 1 nitrogen - free ammonia)
2. OTC - Ornithine transcarbamylase (mitochondria): Carbamoyl phosphate + Ornithine → Citrulline
3. Citrulline exits to cytosol
4. Argininosuccinate synthetase (cytosol): Citrulline + Aspartate + ATP → Argininosuccinate (uses 2nd nitrogen - from aspartate)
5. Argininosuccinate lyase: Argininosuccinate → Arginine + Fumarate
6. Arginase: Arginine + H₂O → Ornithine + Urea

NH₄⁺ + CO₂ + Aspartate + 3 ATP → Urea + Fumarate + 2 ADP + AMP + 4 Pi

• Symptoms: Tremors, slurred speech, vomiting, cerebral edema, coma, death
• Acquired: Liver disease (cirrhosis), portosystemic shunting prevents hepatic clearance
• Congenital urea cycle defects (1:25,000):
  • OTC deficiency (X-linked, most common): ↓ citrulline, ↑ orotic acid (carbamoyl phosphate diverted to pyrimidine synthesis)
  • Citrullinemia type 1 (argininosuccinate synthetase deficiency): ↑ citrulline
  • Argininosuccinic aciduria: ↑ argininosuccinate
  • Arginase deficiency: ↑ arginine
  • CPS-I deficiency: ↑ ammonia, ↓ all downstream intermediates

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4.5 Amino Acid Degradation: Inherited Disorders and Biomolecule Precursors

Carbon Skeleton Catabolism

• Glucogenic AAs (carbon skeleton → glucose via gluconeogenesis): Pyruvate, OAA, fumarate, succinyl-CoA, α-ketoglutarate
• Ketogenic AAs (→ acetyl-CoA or acetoacetate): Only Leucine and Lysine are purely ketogenic
• Both glucogenic and ketogenic: Isoleucine, phenylalanine, tyrosine, tryptophan, threonine

Key Degradation Pathways and Inherited Disorders

• Phenylalanine hydroxylase (PAH) converts Phe → Tyrosine, requiring tetrahydrobiopterin (BH4) as cofactor
• Phenylketonuria (PKU): PAH deficiency → phenylalanine accumulates → excess phenylpyruvate, phenylacetate, phenyllactate. Intellectual disability, musty body odor, fair skin/hair (decreased tyrosine → decreased melanin). Treatment: low-phenylalanine diet lifelong; tetrahydrobiopterin (sapropterin) for BH4-responsive variants.
• Tyrosine is precursor to melanin (via tyrosinase), thyroid hormones (T3, T4), catecholamines (dopamine, epinephrine, norepinephrine), and fumarate/acetoacetate
• Albinism: Tyrosinase deficiency → no melanin; photophobia, skin cancer risk

• Catabolized primarily in muscle (unlike most other AAs which are catabolized in liver)
• BCKD complex (branched-chain α-keto acid dehydrogenase) is analogous to pyruvate dehydrogenase
• Maple Syrup Urine Disease (MSUD): BCKD deficiency → BCAAs + their α-keto acids accumulate. Feeding problems, neurologic damage, maple syrup odor of urine (from isoleucine), fatal if untreated. Treatment: BCAA-restricted formula; thiamine supplements in B1-responsive variants.

• Methionine → SAM (S-adenosylmethionine, the major methyl donor) → homocysteine
• Homocystinuria: Cystathionine β-synthase deficiency → homocysteine accumulates → lens dislocation (ectopia lentis), intellectual disability, osteoporosis, thromboembolism. B6-responsive form (most common). Also caused by deficiency of MTHFR or vitamin B12/folate (impairs remethylation).

• Precursor to serotonin (5-HT), melatonin, niacin (B3, via kynurenine pathway)
• Pellagra: Niacin deficiency (or tryptophan deficiency) → Dermatitis, Diarrhea, Dementia, Death ("4 D's")

• Precursor to heme (as δ-aminolevulinate with succinyl-CoA), purines, glutathione, creatine, bile acids, collagen

Amino Acids as Precursors of Biomolecules

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4.6 Heme Synthesis/Degradation and Nucleotide Metabolism

Heme Synthesis

1. δ-Aminolevulinate (δ-ALA) synthase (mitochondria, committed and rate-limiting step): Succinyl-CoA + Glycine → δ-ALA (requires PLP/vitamin B6)
   • Two isoforms: Hepatic (ALAS1, regulated by heme feedback) and Erythroid (ALAS2, regulated by iron)
   • Induced by drugs (e.g., phenobarbital) and ethanol in hepatic form
   • Inhibited by heme (end-product inhibition) in the hepatic form
2. 2 δ-ALA → Porphobilinogen (PBG) - in cytosol
3. 4 PBG → Uroporphyrinogen III (via HMB and uroporphyrinogen III synthase)
4. Uroporphyrinogen III → Coproporphyrinogen III (uroporphyrinogen decarboxylase, UROD)
5. Coproporphyrinogen III → Protoporphyrinogen IX (returns to mitochondria)
6. Protoporphyrinogen IX → Protoporphyrin IX (oxidation)
7. Protoporphyrin IX + Fe²⁺ → Heme (ferrochelatase, inhibited by lead)

• Acute Intermittent Porphyria (AIP): Porphobilinogen deaminase deficiency. Acute attacks: abdominal pain, neuropsychiatric symptoms, motor neuropathy. Precipitated by drugs (barbiturates, alcohol), fasting. No photosensitivity. Treatment: IV glucose + hemin (suppress ALAS1).
• Porphyria Cutanea Tarda (PCT): UROD deficiency, precipitated by ethanol, hepatitis C, estrogens. Blistering photosensitivity, dark urine (uroporphyrins). Most common porphyria.
• Lead poisoning inhibits ferrochelatase and δ-ALA dehydratase → anemia + elevated δ-ALA in urine.

Heme Degradation

1. Globin → amino acids (recycled)
2. Iron → recycled (stored as ferritin/hemosiderin; transported by transferrin)
3. Heme ring opened by heme oxygenase → Biliverdin (green) + CO + Fe²⁺
4. Biliverdin + NADPH → Unconjugated bilirubin (UCB, yellow) by biliverdin reductase
5. UCB is lipophilic, binds albumin, transported to liver
6. In hepatocytes, UCB is conjugated with 2 glucuronate (via UDP-glucuronosyltransferase, UGT1A1) → Conjugated bilirubin (CB, water-soluble, direct bilirubin)
7. CB secreted into bile → intestine
8. Intestinal bacteria convert CB → urobilinogen → stercobilin (brown color of feces)
9. Some urobilinogen reabsorbed → enterohepatic circulation → excreted in urine as urobilin (yellow)

• Prehepatic (hemolytic): ↑ UCB. Normal stools (dark), ↑ urobilinogen, no bilirubin in urine
• Hepatic: ↑ UCB + ↑ CB. ↑ AST/ALT. Pale stools, dark urine
• Posthepatic (obstructive): ↑ CB. Pale stools (no stercobilin), dark urine (conjugated bilirubin in urine = bilirubinuria), ↓/absent urobilinogen
• Neonatal jaundice: Immature UGT1A1 → UCB accumulates (can cross BBB → kernicterus). Treatment: phototherapy (converts UCB to lumirubin, water-soluble isomer).
• Gilbert syndrome: Mild UGT1A1 deficiency. Benign, intermittent UCB elevation (fasting, illness).
• Crigler-Najjar syndrome type I: Absent UGT1A1 activity; fatal without liver transplant.

Nucleotide Metabolism

• Built on a ribose-5-phosphate scaffold, starting from PRPP (5-phosphoribosyl-1-pyrophosphate)
• Atoms contributed by: Glutamine (N3, N9), Glycine (C4, C5, N7), Aspartate (N1), Formate (C2, C8, via N10-formyl-THF), CO₂ (C6)
• First unique purine product: IMP (inosine monophosphate)
• IMP → AMP (needs GTP + aspartate) or GMP (needs ATP + glutamine)
• Inhibitors: Sulfonamides, methotrexate, azaserine (glutamine analog)

• HGPRT (hypoxanthine-guanine phosphoribosyltransferase) recycles hypoxanthine + PRPP → IMP/GMP
• APRT recycles adenine → AMP
• Lesch-Nyhan syndrome: HGPRT deficiency (X-linked) → purines not salvaged → all degraded to uric acid → severe gout + self-mutilating behavior + neurologic problems

• AMP → IMP → Hypoxanthine → Xanthine → Uric acid (via xanthine oxidase)
• GMP → Guanosine → Guanine → Xanthine → Uric acid
• Gout: Uric acid (relatively insoluble at physiologic pH) deposits as monosodium urate crystals in joints → inflammatory arthritis. Diagnosed by polarized light microscopy (needle-shaped negatively birefringent crystals).
  • Treatments: Acute - colchicine, NSAIDs, corticosteroids; Chronic - allopurinol (xanthine oxidase inhibitor), febuxostat (xanthine oxidase inhibitor), probenecid (uricosuric agent), pegloticase

• The ring is made first, then attached to ribose (unlike purines)
• Regulated step: Carbamoyl phosphate synthetase II (CPS-II), inhibited by UTP, activated by PRPP
• UMP is the precursor of all pyrimidines: UMP → UDP → UTP (and CTP via CTP synthetase); dUMP → dTMP (thymidylate synthase, requires N5,N10-methylene-THF, inhibited by 5-fluorouracil/5-FU)
• Dihydroorotate dehydrogenase (DHODH) is the mitochondrial enzyme; leflunomide (used in rheumatoid arthritis) inhibits it
• Orotic aciduria (hereditary): UMP synthase deficiency → orotic acid in urine + megaloblastic anemia. Treatment: uridine supplementation. (Distinguished from OTC deficiency by presence of hyperammonemia in OTC but not in orotic aciduria)

• Purines → uric acid (excreted in urine)
• Pyrimidines → water-soluble products (malonyl-CoA, β-aminoisobutyrate, NH₃, CO₂) - no gout from pyrimidines

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4.7 Integration of Carbohydrate and Lipid Metabolism: Insulin, Glucagon, Diabetes, Obesity

Integration of Carbohydrate and Lipid Metabolism

• Acetyl-CoA is the convergence point: derived from glucose (pyruvate dehydrogenase), fatty acids (beta-oxidation), and some amino acids; feeds TCA cycle, cholesterol synthesis, or ketogenesis.
• Citrate exported from mitochondria → cytosolic acetyl-CoA for fatty acid synthesis; activates ACC
• Malonyl-CoA - the first committed intermediate of FA synthesis - simultaneously inhibits CPT-I (blocks FA oxidation). This ensures FA synthesis and oxidation don't occur simultaneously.
• When carbohydrate is abundant: glycolysis active → acetyl-CoA → FA synthesis + TCA cycle. Insulin drives GLUT-4 to cell surface, activates glycogen synthase, ACC, FAS.
• When fasting: glucagon/epinephrine → glycogenolysis, gluconeogenesis, lipolysis, FA oxidation, ketogenesis.

Metabolic Effects of Insulin

Metabolic Effects of Glucagon

The Feed-Fast Cycle

• High insulin, low glucagon
• Glucose oxidized for energy; excess → glycogen (liver, muscle) and TAG (adipose)
• Liver: active glycolysis, FA synthesis, VLDL secretion
• Adipose: active FA esterification → TAG storage
• Muscle: active glucose uptake, protein synthesis

• Falling insulin, rising glucagon
• Liver glycogenolysis → blood glucose maintained
• Adipose: lipolysis begins → FFA released → tissues shift to FA oxidation
• Brain still using glucose; liver begins gluconeogenesis (from alanine, lactate, glycerol)

• Very low insulin, high glucagon + cortisol + growth hormone
• Muscle protein catabolism accelerates → gluconeogenic amino acids
• Liver: heavy ketogenesis; ketone bodies become major brain fuel
• Brain adapts to use 3-hydroxybutyrate (reduces glucose demand → reduces protein catabolism)

Diabetes Mellitus

• Impaired GLUT-4 translocation in muscle and adipose
• Elevated FFA → ceramide and DAG accumulation → serine phosphorylation of IRS-1 → insulin signaling blocked
• Ectopic fat in liver → NAFLD → hepatic insulin resistance
• Glucotoxicity and lipotoxicity → β-cell exhaustion

Obesity

• Defined as BMI ≥30 kg/m²
• Excess caloric intake → chronic insulin elevation → chronically active lipogenesis in adipose and liver
• Adipose tissue is not merely a passive storage depot - it is an active endocrine organ secreting adipokines:
  • Leptin (signals satiety to hypothalamus; deficient or resistant in obesity)
  • Adiponectin (↓ in obesity; promotes FA oxidation and insulin sensitivity)
  • Resistin, TNF-α, IL-6 (elevated in obesity; promote insulin resistance)
• Metabolic syndrome: Cluster of central obesity + insulin resistance + hypertension + dyslipidemia (↑ TAG, ↓ HDL) + fasting hyperglycemia → major risk for T2DM and cardiovascular disease
• Non-alcoholic fatty liver disease (NAFLD): Excess acetyl-CoA → TAG synthesis in liver overwhelms VLDL secretory capacity → fat deposits → steatohepatitis (NASH) → cirrhosis

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