Introduction to Lipid Metabolism: Lipogenesis and Lipolysis

Vocabulary practice flashcards covering dietary lipid digestion, absorption, fatty acid and triacylglycerol synthesis (lipogenesis), beta-oxidation (lipolysis), energy yields, and associated metabolic disorders.

Lipids

A group of naturally occurring molecules (including fats, waxes, sterols, fat-soluble vitamins, monoglycerides, diglycerides, triglycerides, and phospholipids) that are insoluble in water but soluble in organic solvents such as ether, benzene, acetone, and chloroform.

Natural Fatty Acid Configuration

The structural arrangement where double bonds in naturally occurring unsaturated fatty acids are found in the cis configuration, whereas trans double bonds predominate in artificially produced foods.

Triglycerides (Triacylglycerols)

Nonpolar storage forms of lipids stored in adipose tissue, composed of glycerol esterified with three fatty acids, yielding approximately $9\,\text{kcal/gm}$ ($38\,\text{kJ/gm}$) upon complete oxidation.

Pancreatic Lipase

A digestive enzyme secreted by the pancreas that cleaves fatty acids specifically at carbons $1$ and $3$ of triacylglycerol (TAG) molecules, producing a mixture of $2\text{-monoacylglycerol}$ and free fatty acids.

Colipase

A protein secreted as pro-colipase by the pancreas that binds to and anchors pancreatic lipase to the surface of the dietary lipid droplet in the presence of bile salts.

Orlistat

An anti-obesity drug that inhibits gastric and pancreatic lipases, decreasing intestinal fat absorption to promote weight loss.

Cholesteryl Ester Hydrolase (Cholesterol Esterase)

A pancreatic enzyme whose activity is greatly enhanced by bile salts, responsible for hydrolyzing dietary cholesteryl esters into free cholesterol and free fatty acids.

Phospholipase A2

An enzyme that removes the fatty acid at carbon $2$ of a phospholipid, converting phosphatidylcholine into lysophosphatidylcholine.

Lysophospholipase

An enzyme that removes the remaining fatty acid at carbon $1$ of a lysophospholipid, yielding glycerylphosphorylcholine.

Mixed Micelles

Aggregates formed by free fatty acids, free cholesterol, $2\text{-monoacylglycerol}$, bile salts, and fat-soluble vitamins ($A$, $D$, $E$, and $K$) with hydrophilic outer surfaces that transport hydrophobic lipids to the intestinal brush border membrane for absorption.

Chylomicrons

Lipoprotein particles synthesized in enterocytes containing resynthesized TAGs and cholesteryl esters surrounded by phospholipids, unesterified cholesterol, and apolipoprotein B-48, released via exocytosis into lymphatics.

Steatorrhea

Lipid malabsorption characterized by excess fat in the stool, caused by a lack of conjugated bile salts, pancreatic juice defects (such as enzyme deficiency, cystic fibrosis, or lack of bicarbonate), or defective mucosal uptake.

Cholecystokinin (CCK)

A gut peptide hormone that stimulates pancreatic enzyme secretion, promotes bile production, and induces gallbladder contraction to discharge bile into the duodenum, while slowing gastric motility.

Secretin

A gut hormone released into the blood that stimulates the pancreas to secrete bicarbonate and fluid components to neutralize acidic contents in the duodenum.

Short-Chain Fatty Acids (SCFA)

Fatty acids having a total carbon-chain length between $1$ and $6$ carbon atoms.

Medium-Chain Fatty Acids (MCFA)

Fatty acids having a total carbon-chain length between $7$ and $12$ carbon atoms.

Long-Chain Fatty Acids (LCFA)

Fatty acids having a total carbon-chain length between $13$ and $20$ carbon atoms.

Very Long-Chain Fatty Acids (VLCFA)

Fatty acids having a total carbon-chain length of more than $20$ carbon atoms ($\ge 22$ carbon atoms).

ATP-Citrate Lyase

A cytosolic enzyme that cleaves citrate transported from the mitochondria into cytosolic oxaloacetate (OAA) and acetyl-CoA, driven by the hydrolysis of ATP.

Malic Enzyme

An enzyme that oxidatively decarboxylates malate to pyruvate in the cytosol, generating a molecule of NADPH and $\text{CO}_2$ to support fatty acid synthesis in liver and adipose tissue.

Acetyl-CoA Carboxylase (ACC)

The rate-limiting enzyme of fatty acid synthesis that carboxylates acetyl-CoA into malonyl-CoA; an ABC enzyme requiring ATP, Biotin (vitamin B7), and $\text{CO}_2$, activated by insulin, dephosphorylation, and citrate, and inhibited by glucagon, epinephrine, AMPK phosphorylation, and palmitoyl-CoA.

Malonyl-CoA

A $3\text{-carbon}$ intermediate produced by acetyl-CoA carboxylase that serves as the two-carbon donor during fatty acid chain elongation and allosterically inhibits carnitine palmitoyltransferase I (CPT-I) to block simultaneous beta-oxidation.

Fatty Acid Synthase (FAS)

A multifunctional $260\,\text{kDa}$ homodimeric enzyme complex where each monomer contains seven distinct enzymatic activities and an acyl carrier protein (ACP) containing pantothenic acid (vitamin B5), responsible for synthesizing palmitate (C16:0).

Palmitate Synthesis Stoichiometry

The complete reaction sequence for palmitate formation: $\text{Acetyl-CoA} + 7\,\text{malonyl-CoA} + 14\,\text{NADPH} + 14\,\text{H}^+ \rightarrow \text{Palmitate} + 7\,\text{CO}_2 + 14\,\text{NADP}^+ + 8\,\text{CoA-SH} + 6\,\text{H}_2\text{O}$, requiring $7$ rounds of elongation.

Fatty Acid Elongase

An enzyme located mainly in the endoplasmic reticulum that condenses acyl-CoA with malonyl-CoA, utilizing $2\,\text{NADPH}$ per added two-carbon unit to lengthen fatty acid chains beyond $16$ carbons.

Fatty Acid Desaturases

Enzymes in the endoplasmic reticulum (possessing $\Delta^4$, $\Delta^5$, $\Delta^6$, and $\Delta^9$ activities in humans) that introduce cis double bonds into fatty acids using cytochrome $b_5$, NADH-cytochrome $b_5$ reductase, and molecular oxygen; cannot introduce double bonds beyond carbon $9$.

Glycerol Kinase

An enzyme present in hepatocytes that phosphorylates free glycerol to glycerol-3-phosphate for TAG synthesis; it is absent in adipose tissue, forcing adipocytes to rely on glucose uptake and glycolysis (DHAP) for TAG production.

Hormone-Sensitive Lipase (HSL)

The key regulatory enzyme of lipolysis in adipose tissue that hydrolyzes stored TAGs; active in the phosphorylated state via cAMP/PKA upon stimulation by epinephrine and low insulin during fasting, and inhibited by insulin in the fed state.

Niacin (Antihyperlipidemic Action)

A pharmacological agent that at high doses inhibits hormone-sensitive lipase in adipose tissue, reducing circulating free fatty acids to the liver, thereby decreasing hepatic VLDL synthesis and subsequent serum LDL levels.

Carnitine Palmitoyltransferase I (CPT-I)

An outer mitochondrial membrane enzyme that converts cytosolic fatty acyl-CoA into fatty acyl-carnitine for transport into the mitochondria; acts as the rate-limiting step of beta-oxidation and is inhibited by malonyl-CoA.

Carnitine Palmitoyltransferase II (CPT-II)

An inner mitochondrial membrane enzyme that transfers the fatty acyl moiety from acyl-carnitine back to mitochondrial CoA, reforming fatty acyl-CoA inside the matrix for beta-oxidation.

Beta-Oxidation Cycle

A four-step mitochondrial sequence involving the $\beta\text{-carbon}$ of fatty acyl-CoA: (1) oxidation by acyl-CoA dehydrogenase ($\text{FAD}\rightarrow\text{FADH}_2$), (2) hydration by enoyl-CoA hydratase, (3) oxidation by 3-hydroxyacyl-CoA dehydrogenase ($\text{NAD}^+\rightarrow\text{NADH}+\text{H}^+$), and (4) thiolytic cleavage by thiolase.

Net Energy Yield of Palmitate Oxidation

Complete beta-oxidation of $16\text{C}$ palmitic acid produces $8\,\text{acetyl-CoA}$ ($96\,\text{ATP}$), $7\,\text{FADH}_2$ ($14\,\text{ATP}$), and $7\,\text{NADH}$ ($21\,\text{ATP}$), totaling $131\,\text{ATP}$, which results in a net of $129\,\text{ATP}$ after subtracting $2\,\text{ATP}$ for activation.

Omega-Oxidation (ω-Oxidation)

A minor alternative fatty acid oxidation pathway occurring in the endoplasmic reticulum that oxidizes the $\omega\text{-carbon}$ to produce dicarboxylic acids, which accumulate in blood and urine when beta-oxidation is impaired.

Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency

An autosomal recessive disorder impairing oxidation of $6\text{ to }12\text{-carbon}$ fatty acids, leading to severe hypoketotic hypoglycemia, elevated $C_8\text{--}C_{10}$ acylcarnitines in blood, urinary dicarboxylic acids, vomiting, lethargy, seizures, and hyperammonemia.

Systemic Carnitine Deficiency

An autosomal recessive disorder characterized by impaired carnitine uptake into tissues, blocking long-chain fatty acid transport into mitochondria and resulting in hypoketotic hypoglycemia, seizures, arrhythmias, and SIDS within hours of life.

Myopathic CPT-II Deficiency

An autosomal recessive adult- or adolescent-onset disease affecting Type I (slow twitch) skeletal muscle fibers, presenting with muscle aches, weakness, rhabdomyolysis, myoglobinuria (red urine), and lipid droplets on biopsy following prolonged exercise or fasting.

Hypoglycin A

A toxin found in the unripened fruit of the ackee tree that inhibits fatty acyl-CoA dehydrogenase, causing Jamaican vomiting sickness and profound hypoglycemia $2\text{--}6\,\text{hours}$ after ingestion.

Propionyl-CoA

A $3\text{-carbon}$ product generated in the final round of odd-chain fatty acid beta-oxidation, which is subsequently converted into succinyl-CoA via propionyl-CoA carboxylase and methylmalonyl-CoA mutase to enter the TCA cycle.

Peroxisomal Beta-Oxidation

The preliminary catabolic pathway for very long-chain fatty acids ($\ge 22\,\text{carbons}$) initiated by FAD-containing acyl-CoA oxidase, which generates $\text{H}_2\text{O}_2$ (degraded by catalase) instead of ATP, until the shortened chain can diffuse to mitochondria.

Zellweger Syndrome

An autosomal recessive cerebrohepatorenal disorder caused by mutations in PEX genes leading to defective peroxisome biogenesis, characterized by elevated circulating $C_{26}$ fatty acids, neonatal hypotonia, seizures, craniofacial dysmorphism, hepatomegaly, PKD, and death within the first year.

Phytanic Acid

A $20\text{-carbon}$ branched-chain dietary fatty acid found in dairy products that cannot undergo direct beta-oxidation due to a methyl group on its $\beta\text{-carbon}$, requiring peroxisomal alpha-oxidation by phytanoyl-CoA hydroxylase (PhyH) to yield $19\text{-carbon}$ pristanic acid.

Refsum Disease

An autosomal recessive defect in peroxisomal alpha-oxidation causing the accumulation of phytanic acid, presenting with retinitis pigmentosa (night blindness), symmetrical ascending polyneuropathy, ataxia, anosmia, ichthyosis, sensorineural hearing loss, and a shortened fourth toe.

Adrenoleukodystrophy (ALD)

An X-linked recessive disorder caused by mutations in the ABCD1 gene encoding a peroxisomal ABC transporter protein, leading to defective transport and beta-oxidation of VLCFA, resulting in VLCFA accumulation, neuronal demyelination, cognitive deterioration, and adrenal insufficiency.