lipids
Digestive processing, absorption, and transport of lipids
Fats are not very soluble in water; digestion requires emulsification and enzymatic action in the intestine.
Initial digestion begins with lingual and gastric lipases, especially in infants. The bulk of digestion occurs in the small intestine.
Emulsification and micelle formation- Emulsification of dietary triacylglycerols (TAGs) in the small intestine is mediated by bile salts (biological detergents) which break down large fat globules into smaller ones.
Pancreatic lipase, aided by colipase, hydrolyzes TAGs to free fatty acids (FAs) and monoacylglycerols (MAG).
These products interact with bile salts to form tiny micelles, increasing their surface area for absorption into intestinal epithelial cells.
Absorption and reassembly- Fatty acids and MAGs are absorbed by intestinal epithelial cells (enterocytes) by diffusing across the brush border membrane, aided by fatty acid binding proteins.
Inside enterocytes, these FAs and MAGs are re-esterified to TAGs in the endoplasmic reticulum and then assembled with proteins, phospholipids, cholesterol, and other components into lipoprotein particles called chylomicrons in the Golgi apparatus.
Transport from gut to tissues- Chylomicrons are secreted into the lymphatic system (lacteals) and then enter the bloodstream through the thoracic duct.
Fatty acids from chylomicron TAGs, after hydrolysis by lipoprotein lipase, are stored mainly as TAGs in adipose tissue or oxidized for energy or used for membrane lipid synthesis in other tissues.
Apolipoproteins (apo-lipoproteins)
Apo-lipoproteins are the protein components of lipoproteins (apo-Lp) or apoproteins:
Apo-AI: Major apoprotein of HDL; acts as a ligand for HDL receptor and activates Lecithin-cholesterol acyltransferase (LCAT), which is crucial for HDL maturation, giving it anti-atherogenic properties.
Apo-B-100: Major apoprotein of LDL and VLDL; essential for the structural integrity of LDL and binds to the LDL receptor on tissues to facilitate cellular uptake.
Apo-B-48: Major apoprotein of chylomicrons; synthesized in intestinal cells and necessary for chylomicron secretion from enterocytes.
Apo-C-II: Transfers from HDL to chylomicrons and VLDL; it is a critical activator of lipoprotein lipase (LpL), allowing hydrolysis of TAGs.
Apo-E: Arginine-rich protein present in chylomicrons, LDL, and VLDL; acts as a ligand for the LDL receptor and LDL Receptor-related Protein 1 (LRP1), involved in cellular transport of lipids in CNS and crucial for remnant clearance via hepatic receptors.
Metabolism of chylomicrons
Initial activation and hydrolysis- As chylomicrons circulate, they acquire apo-C-II and apo-E from HDL. Apo-C-II on chylomicrons activates LpL (lipoprotein lipase), which is located on the luminal surface of capillaries in adipose tissue and muscle.
LpL hydrolyzes TAGs in chylomicrons to fatty acids and glycerol; liberated FAs are taken up by muscle/adipose tissue for energy or storage. Glycerol is returned to the liver.
Remnant clearance- As TAG content is depleted, chylomicrons shrink and transfer apo-C-II back to HDL, becoming chylomicron remnants containing apoB-48 and apoE.
Hepatic cells take up remnants via receptor-mediated endocytosis, primarily recognizing apoE by the hepatic LDL receptor and LDL Receptor-related Protein 1 (LRP1).
Very Low Density Lipoproteins (VLDL), IDL, and LDL
VLDL synthesis and composition- VLDL is synthesized in the liver from glycerol, fatty acids (endogenous TAGs), hepatic cholesterol, apo-B-100, apo-C-II, and apo-E. It is the primary transport vehicle for endogenously synthesized TAGs.
Apo-B-100 is the major apoprotein present in VLDL at secretion; Apo-E and Apo-C-II are supplied by HDL in plasma.
Metabolism of VLDL and conversion to IDL/LDL- In peripheral tissues, apo-C-II activates LpL, releasing fatty acids for uptake by adipose and muscle cells.
As VLDL loses TAGs, it becomes denser and is called a VLDL remnant, also known as Intermediate Density Lipoprotein (IDL), with less TAG and a higher proportion of cholesterol.
IDL can be taken up by the liver or be further depleted of TAGs by hepatic lipase (HL) to form Low Density Lipoprotein (LDL), the major cholesterol carrier to peripheral tissues.
Function of VLDL/LDL- VLDL carries endogenous TAGs from the liver to peripheral tissues for energy needs or storage.
LDL transports cholesterol from the liver to peripheral tissues, where it is used for membrane synthesis, steroid hormone production, or stored. LDL receptor-mediated endocytosis clears LDL from plasma.
Low Density Lipoproteins (LDL) and LDL receptors
LDL composition and uptake- LDL contains only apo-B-100 as the apoprotein, making it the primary ligand for LDL receptors.
LDL receptors (primarily in hepatic cells, but also in peripheral tissues) mediate uptake of LDL via a process involving clathrin-coated pits. This is the main mechanism for removing cholesterol from the blood.
Binding of apo-B-100 to the LDL receptor on the cell surface enables endocytosis of the LDL-receptor complex into the cell. Inside the cell, the LDL and receptor dissociate, with the receptor recycling to the surface and LDL being degraded in lysosomes to release cholesterol, fatty acids, and amino acids.
LDL function and fate- About of plasma cholesterol is carried by LDL particles.
Cholesterol delivered to cells is used for steroid synthesis, membrane synthesis, or other needs. Intracellular cholesterol also regulates its own supply by downregulating HMG-CoA reductase (the rate-limiting enzyme in cholesterol synthesis) and the synthesis of new LDL receptors, as well as activating acyl-CoA cholesterol acyltransferase (ACAT) for cholesterol storage.
High Density Lipoprotein (HDL)
Synthesis of HDL- Nascent HDL particles (disk-shaped, rich in phospholipids and apo-AI) are formed in the liver and intestine. They acquire lipids (cholesterol and phospholipids) from other lipoproteins and cell membranes.
Maturation- As nascent HDL circulates, apo-AI activates Lecithin-cholesterol acyltransferase (LCAT), which esterifies free cholesterol donated by cells (via ABCA1 transporter) to cholesteryl esters. The more hydrophobic cholesteryl esters move to the core of the HDL, causing it to become spherical and mature.
Function- Major role: reverse cholesterol transport — HDL removes excess cholesterol from cholesterol-laden cells (e.g., macrophages in the arterial wall) via ABCA1 and SR-B1 transporters and returns it to the liver directly (via SR-B1 receptor) or indirectly through the action of Cholesteryl Ester Transfer Protein (CETP), which exchanges cholesteryl esters from HDL for TAGs from VLDL or LDL. This process helps prevent cholesterol accumulation in arteries.
Fatty acid oxidation and ketone body metabolism
General pathway- When dietary fatty acids exceed needs, the liver converts excess FAs to TAGs and packages them into VLDL for transport to adipose tissue.
Fatty acids are oxidized for energy in tissues or re-esterified for storage.
Fatty acid oxidation (β-oxidation) in the mitochondria- The primary pathway for breaking down fatty acids into acetyl-CoA.
Activation: Fatty acids are activated to acyl-CoA in the cytosol by acyl-CoA synthetase (thiokinase), utilizing 2 high-energy phosphate bonds from ATP (ATP $\to$ AMP + ). The reaction looks like:
ext{FA} + ext{CoA} + 2\,\text{ATP} \rightarrow \text{acyl-CoA} + \text{AMP} + 2\,\text{P_i}
Transport: Long-chain acyl-CoAs cannot directly cross the inner mitochondrial membrane. They are transported into the mitochondrial matrix via the carnitine shuttle. Carnitine palmitoyltransferase I (CPT-I) on the outer mitochondrial membrane converts acyl-CoA to acylcarnitine. Acylcarnitine is transported into the matrix by carnitine-acylcarnitine translocase, where CPT-II on the inner mitochondrial membrane reforms acyl-CoA.
Oxidation (β-oxidation cycle): Each cycle involves four sequential reactions that shorten the fatty acyl-CoA by 2 carbons, producing 1 FADH$_2$, 1 NADH, and releasing 1 acetyl-CoA. The cycle repeats until the entire fatty acid is converted to acetyl-CoA.
Dehydrogenation: Acyl-CoA dehydrogenase introduces a trans-double bond between C2 and C3, forming trans-Δ2-enoyl-CoA and FADH$_2$.
Hydration: Enoyl-CoA hydratase adds water across the double bond, forming L-β-hydroxyacyl-CoA.
Dehydrogenation: L-β-hydroxyacyl-CoA dehydrogenase oxidizes the hydroxyl group to a keto group, forming β-ketoacyl-CoA and NADH.
Thiolysis: β-ketoacyl-CoA thiolase cleaves the β-ketoacyl-CoA, releasing acetyl-CoA and a fatty acyl-CoA shortened by two carbons.
Energetics for saturated even-number fatty acids- Each FADH$_2$ yields per molecule; each NADH yields per molecule (via oxidative phosphorylation).
Each β-oxidation cycle directly yields a net of from cofactors (2.5 from NADH + 1.5 from FADH$_2$). The acetyl-CoA produced then enters the TCA cycle for further ATP generation.
Palmitic acid (C$_{16}$:0) example: A 16-carbon fatty acid undergoes 7 cycles of β-oxidation and produces 8 molecules of acetyl-CoA.
Activation cost: (for the initial activation)
β-oxidation cycles: (This accounts for the FADH$_2$ and NADH produced per cycle and a small theoretical contribution from acetyl-CoA oxidation, as stated in the quick reference previously.)
Acetyl-CoA entering TCA: (each acetyl-CoA yields about 12 ATP via the TCA cycle and oxidative phosphorylation)
Net total:
Ketone bodies- Ketogenesis occurs in the liver mitochondria when there is an excess of acetyl-CoA (e.g., during prolonged fasting or uncontrolled diabetes) from extensive FA oxidation that exceeds the capacity of the TCA cycle. Excess acetyl-CoA is converted to ketone bodies (acetoacetate, 3-hydroxybutyrate, and acetone).
Ketone bodies are exported from the liver to extrahepatic tissues (like muscle and brain) where they are converted back to acetyl-CoA for energy (ketolysis).
Acetone is produced in smaller quantities by spontaneous decarboxylation of acetoacetate and is exhaled.
The brain can adapt to use ketone bodies as a significant fuel source during starvation when glucose is limited, becoming especially crucial when glucose stores run low.
Odd-numbered and poly-unsaturated fatty acids
Odd-numbered saturated FA and propionyl-CoA metabolism- Odd-numbered saturated FAs, upon β-oxidation, yield propionyl-CoA (a 3-carbon unit) as the final product of the last cycle, in addition to acetyl-CoA units. Propionyl-CoA is converted to succinyl-CoA and enters the TCA cycle after conversion to oxaloacetate.
This conversion involves a carboxylation reaction by propionyl-CoA carboxylase (requiring biotin) to D-methylmalonyl-CoA; then an isomerase converts D-methylmalonyl-CoA to L-methylmalonyl-CoA; finally, methylmalonyl-CoA mutase (requiring vitamin B12) forms succinyl-CoA.
Monounsaturated and polyunsaturated FA catabolism- Mono-unsaturated FAs: cis double bonds at or near C3 require an additional enzyme, enoyl-CoA isomerase, to move the double bond and convert the cis-configuration to a trans-Δ2-enoyl-CoA, which can then proceed through standard β-oxidation.
Polyunsaturated FAs require both isomerase and 2,4-dienoyl-CoA reductase (requiring NADPH) for proper processing, as they have multiple double bonds, some of which are often in a cis and non-conjugate configuration that β-oxidation enzymes cannot directly process.
Iterative degradation with multiple spirals- PUFA degradation can involve multiple β-oxidation spirals, with isomerase/reductase enabling continued processing of cis bonds by repositioning them into the trans-Δ2 configuration required by the standard β-oxidation pathway.
Propionate metabolism and inborn errors
Propionyl-CoA carboxylase deficiency and methylmalonic aciduria- Propionic acidemia is a severe metabolic disorder that can result from a deficiency in propionyl-CoA carboxylase, leading to the accumulation of propionic acid and subsequently ketoacidosis. This can also lead to hyperammonemia, developmental delay, and seizures.
Methylmalonic aciduria involves impaired methylmalonyl-CoA metabolism, often due to a defect in methylmalonyl-CoA mutase or a deficiency in its cofactor, vitamin B12. There are responsive and non-responsive forms to B$_{12}$ depending on the specific mutase or racemase defects.
Brain metabolism is significantly affected in these conditions, potentially leading to mental retardation and neurological damage if not promptly diagnosed and managed with dietary restriction and cofactor supplementation.
Ketone body synthesis and utilization; ketolysis
Ketogenesis in liver- High acetyl-CoA levels in liver mitochondria lead to the condensation of two acetyl-CoA molecules to form acetoacetyl-CoA, catalyzed by thiolase. Acetoacetyl-CoA then condenses with another acetyl-CoA to form HMG-CoA (catalyzed by HMG-CoA synthase). HMG-CoA lyase cleaves HMG-CoA to acetoacetate and acetyl-CoA. Acetoacetate can then be reduced to 3-hydroxybutyrate (via β-hydroxybutyrate dehydrogenase, using NADH) or spontaneously decarboxylate to acetone.
Ketolysis in peripheral tissues- Peripheral tissues (e.g., muscle, heart, brain during starvation) convert acetoacetate back to acetyl-CoA for energy. Acetoacetate is converted to acetoacetyl-CoA via succinyl-CoA:acetoacetate-CoA transferase (also known as thiophorase), which transfers CoA from succinyl-CoA. Acetoacetyl-CoA is then cleaved by thiolase to two molecules of acetyl-CoA, which can enter the TCA cycle. The liver cannot utilize ketone bodies because it lacks thiophorase.
Clinical notes- Ketone bodies rise during fasting, prolonged strenuous exercise, or poorly controlled diabetes (Type 1 diabetes, in particular, due to insulin deficiency). Diabetic ketoacidosis (DKA) can be life-threatening, characterized by severe metabolic acidosis, electrolyte shifts, dehydration, and can lead to ketoacidotic coma if not treated promptly with insulin and fluid/electrolyte replacement.
Fatty acid synthesis (lipogenesis) and the fatty acid synthase system
Overview- Fatty acid synthesis is primarily catalyzed by fatty acid synthase (FAS), a cytosolic multifunctional enzyme complex found in the liver, adipose tissue, and lactating mammary glands.
Acetyl-CoA is the starter molecule; the chain is elongated by two-carbon units derived from malonyl-CoA; NADPH provides reducing equivalents for the synthesis.
Key initiating and regulating enzymes- Acetyl-CoA carboxylase (ACC) is the key enzyme that catalyzes the irreversible carboxylation of acetyl-CoA to malonyl-CoA, the committed step and rate-limiting step in fatty acid synthesis.
ACC is regulated allosterically and hormonally; how that regulation occurs is described below.
Fatty acid synthase mechanism (brief)- FAS is a large, homodimeric enzyme with multiple catalytic domains. The synthesis chain initiates with acetyl-CoA and elongates by sequential addition of 2-carbon units from malonyl-CoA. The main steps are:
Loading: Acetyl-CoA and malonyl-CoA are transferred to the acyl carrier protein (ACP) and ketoacyl synthase (KS) domains of FAS.
Condensation: The acetyl group on KS condenses with the malonyl group on ACP, releasing CO2 and forming a β-ketoacyl-ACP, thus elongating the chain by two carbons.
Reduction (1st): β-ketoacyl-ACP reductase (KR) uses NADPH to reduce the keto group at C3 to a hydroxyl group, forming β-hydroxyacyl-ACP.
Dehydration: β-hydroxyacyl-ACP dehydratase (DH) removes water, creating a double bond, forming trans-Δ2-enoyl-ACP.
Reduction (2nd): Enoyl-ACP reductase (ER) uses NADPH to reduce the double bond, forming a saturated acyl-ACP.
Translocation: The elongated acyl group is transferred from ACP to the KS domain.
Repeat: Another malonyl-CoA loads onto ACP, and the cycle continues, adding 2 carbons in each round, until palmitate (C$_{16}$:0) is formed, which is usually released by thioesterase activity.
Regulation of fatty acid synthesis
Acetyl-CoA carboxylase (ACC) activity- ACC activity is highly regulated allosterically and hormonally; it exists in two forms: an inactive protomer and an active polymer.
Allosteric activator: Citrate, which is produced in the mitochondrial matrix during the TCA cycle and signals an abundance of acetyl-CoA and energy. It activates ACC by promoting its polymerization.
Allosteric inhibitor: Long-chain acyl-CoA (e.g., palmitoyl-CoA), which is an end-product of fatty acid synthesis, inhibits ACC activity by promoting its depolymerization (feedback inhibition).
Hormonal regulation- Glucagon (and epinephrine) promotes phosphorylation of ACC (via PKA), reducing its activity and thus inhibiting fatty acid synthesis.
Insulin promotes dephosphorylation (via protein phosphatase 2A), activating ACC and promoting fatty acid synthesis (lipogenesis) by signaling a state of energy abundance.
Hormonal control of lipid metabolism
Fed state (insulin-dominated)- When insulin levels are high (after a meal), tissues predominantly use glucose for energy; the liver replenishes glycogen stores; adipose tissue increases TAG synthesis and storage; muscle increases protein synthesis; the brain primarily uses glucose.
Starved or fasting state (glucagon, cortisol, epinephrine-dominated)- During fasting, gluconeogenesis and fatty acid oxidation are upregulated; adipose tissue hydrolyzes TAGs (via hormone-sensitive lipase) to release FA and glycerol into the bloodstream; the liver takes up FAs and converts them to acetyl-CoA, which can then be used for ketone body synthesis; the brain shifts to utilizing ketone bodies for energy when glucose is scarce.
Cholesterol metabolism
Cholesterol synthesis overview- Cholesterol synthesis initiates in the cytosol from acetyl-CoA. Acetate (from acetyl-CoA) is converted through several steps to isoprene units (5-carbon building blocks) with a 30-carbon squalene intermediate that cyclizes to the four-ring cholesterol structure.
Mevalonate pathway (key steps)- The synthesis begins with the condensation of three acetyl-CoA molecules to form HMG-CoA.
The formation of mevalonate from HMG-CoA, catalyzed by HMG-CoA reductase (HMGCR), is the rate-limiting enzyme and a major control point.
Mevalonate is then converted through several ATP-dependent phosphorylation and decarboxylation steps to isopentenyl diphosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are the activated isoprenoid units.
These isoprenoid units then condense sequentially to form geranyl diphosphate (C10), farnesyl diphosphate (C15), and finally, two farnesyl diphosphate molecules condense to form squalene (C30).
Squalene is then cyclized to lanosterol, which undergoes multiple enzymatic modifications to yield cholesterol.
Regulation of cholesterol synthesis- Cholesterol synthesis is meticulously regulated to maintain cellular cholesterol homeostasis.
Feedback control: High intracellular cholesterol levels downregulate HMG-CoA reductase activity and reduce the synthesis of new enzyme molecules, largely through the SREBP (Sterol Regulatory Element-Binding Protein) pathway. When cholesterol is abundant, SREBP is retained in the ER. When cholesterol is low, SREBP moves to the Golgi, is cleaved, and its active fragment translocates to the nucleus to activate transcription of genes for HMG-CoA reductase and LDL receptors.
Hormonal regulation: Glucagon and glucocorticoids favor the inactive (phosphorylated) form of HMG-CoA reductase; insulin and thyroxine promote the active (dephosphorylated) form.
Drug inhibition: Statins (e.g., atorvastatin, simvastatin, pravastatin, etc.) are competitive inhibitors of HMG-CoA reductase, effectively lowering cholesterol synthesis. Bile acids inhibit HMG-CoA reductase activity; fasting also lowers enzyme activity.
Bile acids synthesis and steroid hormones
Bile composition and role- Bile consists mainly of water (), bile salts derived from cholesterol, bile pigments (bilirubin, biliverdin), fats (cholesterol, fatty acids, lecithin), and inorganic salts. Bile salts emulsify dietary fats in the small intestine, aiding in their digestion and absorption.
Gut bacteria convert primary bile acids that escape reabsorption in the ileum to secondary bile acids (e.g., deoxycholate and lithocholate) via deconjugation and 7-dehydroxylation.
Synthesis of bile salts- Bile acid synthesis begins in the liver from cholesterol.
The first and rate-limiting step is the hydroxylation of cholesterol at the 7-alpha position by 7-α-hydroxylase (a microsomal enzyme dependent on NADPH and O2), forming 7α-hydroxycholesterol. This initiates the pathway for primary bile acid synthesis.
Further modifications, including epimerization of the 3β-hydroxyl group to 3α and additional hydroxylation (e.g., at C12 for cholic acid), lead to the formation of the primary bile acids: chenodeoxycholic acid (has OH at 3 and 7 only) and cholic acid (has OH at 3, 7, and 12).
Primary bile acids are then conjugated in the liver with glycine or taurine to form more soluble bile salts (e.g., glycocholate, taurocholate), which are then secreted into bile.
Fate of bile acids- Most bile salts are efficiently reabsorbed in the ileum and returned to the liver via the enterohepatic circulation. Intestinal bacteria can deconjugate and dehydroxylate bile salts, producing secondary bile salts, which are less soluble and less readily reabsorbed and are mostly excreted in the feces.
Steroid hormones biosynthesis and regulation
Steroid hormone biosynthesis pathway- All steroid hormones are synthesized from cholesterol. The common rate-limiting step is the conversion of cholesterol to pregnenolone, catalyzed by cholesterol desmolase (CYP11A1) located in the mitochondria of steroidogenic cells. This step is stimulated by ACTH in the adrenal cortex.
Pregnenolone is then converted to progesterone via 3β-hydroxysteroid dehydrogenase and Δ5-Δ4 isomerase.
Progesterone serves as a central precursor and is further converted to glucocorticoids (e.g., cortisol), mineralocorticoids (e.g., aldosterone), and sex steroids (androgens and estrogens) through multiple specific hydroxylation and cleavage steps, primarily in the adrenal cortex, gonads, and placenta. Each class of steroid hormones involves distinct sets of cytochrome P450 enzymes.
Regulation of adrenal hormone secretion- All adrenocortical hormones are under the regulatory control of Adrenocorticotropic Hormone (ACTH), which is released from the anterior pituitary.
Cortisol, a major glucocorticoid, exhibits a distinct diurnal variation, with highest levels in the morning, linked to the pulsatility of ACTH secretion driven by Corticotropin-Releasing Factor (CRF) from the hypothalamus.
High levels of cortisol exert negative feedback on both ACTH secretion from the pituitary and CRF secretion from the hypothalamus, thereby modulating its own production.
All steroid hormones act through intracellular receptors (either cytoplasmic or nuclear) to alter gene expression by binding to specific DNA sequences (steroid response elements), leading to increased or decreased transcription rates of target genes.
Dyslipidemias, atherosclerosis, and pharmacological targets
Atherosclerosis (basic biochemical basis)- Atherosclerosis is a chronic inflammatory disease characterized by the progressive hardening and narrowing of artery walls due to the formation of plaque, strongly promoted by high levels of LDL cholesterol.
Initial Endothelial Dysfunction: Chronic elevated LDL, hypertension, and other factors lead to endothelial injury or dysfunction, increasing permeability and promoting the expression of adhesion molecules (e.g., VCAM-1, ICAM-1) on the endothelial cell surface.
Monocyte Adhesion and Transmigration: Circulating monocytes adhere to the activated endothelium and migrate into the subendothelial space.
Macrophage Differentiation and Oxidized LDL Uptake: Once in the intima, monocytes differentiate into macrophages. LDL particles become trapped in the subintima and are oxidized (oxLDL). Macrophages internalize oxLDL (primarily via scavenger receptors like SR-A and CD36, not the LDL receptor, which is downregulated by high cholesterol), becoming lipid-laden foam cells.
Fatty Streak Formation: Accumulation of foam cells forms visible fatty streaks, the earliest lesions of atherosclerosis.
Fibrous Cap Formation: Smooth muscle cells migrate from the media into the intima, proliferate, and synthesize extracellular matrix components (collagen, elastin) to form a robust fibrous cap over the lipid core. This stabilizes the plaque.
Plaque Maturation and Rupture: Advanced plaques have a necrotic core and a fibrous cap. Inflammation, proteases (e.g., matrix metalloproteinases) secreted by macrophages, can degrade the fibrous cap, thinning it and making the plaque vulnerable to rupture. Rupture exposes the thrombogenic lipid core and collagen to the blood, triggering acute thrombus formation, which can occlude the artery and lead to myocardial infarction or stroke.
Pharmacological targets and treatment approaches- Hypolipidemic strategies include fundamental lifestyle changes (e.g., diet rich in PUFAs, reduced refined carbohydrates, increased fiber, reduced saturated/trans fats), regular physical exercise, and pharmacological interventions.
Drug classes and mechanisms:
HMG-CoA reductase inhibitors (statins): These are the most effective cholesterol-lowering drugs, e.g., atorvastatin, simvastatin, pravastatin, rosuvastatin, lovastatin, fluvastatin. They competitively inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, leading to decreased hepatic cholesterol production and upregulation of LDL receptors, which increases LDL clearance from the blood.
Fibrates: Activate lipoprotein lipase (LpL) and increase the synthesis of Apo-AI and Apo-II. They primarily reduce plasma TAGs and may raise HDL cholesterol. Examples include fenofibrate, gemfibrozil, clofibrate.
Bile acid sequestrants: Bind to bile acids in the intestine, preventing their reabsorption and increasing their fecal excretion. This interruption of the enterohepatic circulation forces the liver to synthesize new bile acids from cholesterol, thereby depleting hepatic cholesterol stores and upregulating LDL receptors. Examples are cholestyramine, colestipol, colesevelam.
Therapeutic note: Sequestrants reduce intestinal reabsorption of bile acids, thereby lowering plasma cholesterol and LDL levels.
Numerical and conceptual references to review equations and data
Activation step cost in β-oxidation: per fatty acid (due to ATP $\to$ AMP + ).
Palmitate energy yield (example): For a C$_{16}$:0 fatty acid (palmitic acid).
Activation:
β-oxidation cycles (7 cycles): (This accounts for the FADH$_2$ and NADH produced per cycle and a small theoretical contribution from acetyl-CoA oxidation, as stated in the text)
TCA oxidation of acetyl-CoA (8 molecules): (Each acetyl-CoA yields about 12 ATP including TCA cycle and oxidative phosphorylation)
Net energy:
General ATP yields in β-oxidation and TCA: FADH$_2$ $\approx 1.5\text{ ATP}$ per FADH$_2$, NADH $\approx 2.5\text{ ATP}$ per NADH, and each acetyl-CoA entering the TCA cycle yields about (via 3 NADH, 1 FADH$_2$, and 1 GTP).
Connections and real-world relevance
Link to energy metabolism: Lipid digestion, absorption, and lipoprotein transport provide the basis for how dietary fats are processed, distributed, and influence plasma lipid levels and the risk of atherosclerosis. They are essential energy stores and fuel sources.
Health implications: The dynamic regulation of cholesterol and fatty acid synthesis affects overall energy balance, cellular membrane composition, and cell signaling. Dyslipidemias, characterized by abnormal lipid levels, are major contributors to cardiovascular disease risk.
Therapeutic relevance: Targeting key enzymes and pathways involved in lipid metabolism, such as HMG-CoA reductase (statins), LpL activity (fibrates), bile acid sequestration, and fatty acid synthesis enzymes, offers effective strategies to control plasma lipid levels and reduce the risk and progression of related diseases, especially cardiovascular disease.
Quick reference equations and key reactions
TAG digestion to FAs and MAGs in the intestine: catalyzed by pancreatic lipase; emulsification by bile salts forms micelles.
Activation of fatty acids: ext{FA} + \text{CoA} + 2\,\text{ATP} \rightarrow \text{acyl-CoA} + \text{AMP} + 2\,\text{P_i}
β-oxidation cycle (even-number saturated FA): each cycle releases 1 acetyl-CoA, 1 FADH$_2$, and 1 NADH. The four steps are dehydrogenation (FADH$_2$), hydration, dehydrogenation (NADH), and thiolysis (acetyl-CoA release).
Palmitate energy yield: activation (-2 ATP) + 7 cycles (35 ATP) + 8 acetyl-CoA $\times$ 12 ATP (96 ATP) = 129 ATP net.
Cholesterol synthesis route: acetyl-CoA $\rightarrow$ acetoacetyl-CoA $\rightarrow$ HMG-CoA $\rightarrow$ mevalonate (HMG-CoA reductase is rate-limiting) $\rightarrow$ IPP/DMAPP $\rightarrow$ squalene $\rightarrow$ cholesterol.
Ketone body metabolism: acetyl-CoA formed during FA oxidation can be diverted to ketogenesis in liver mitochondria (HMG-CoA synthase/lyase pathway); ketolysis in other tissues regenerates acetyl-CoA for the TCA cycle via thiophorase.
Propionyl-CoA to succinyl-CoA: Propionyl-CoA $\rightarrow$ (propionyl-CoA carboxylase, biotin) D-methylmalonyl-CoA $\rightarrow$ (methylmalonyl-CoA mutase, B12) succinyl-CoA $\rightarrow$ enters TCA.
Bile acid synthesis: cholesterol $\rightarrow$ (7-α-hydroxylase, rate-limiting) primary bile acids; conjugation with glycine/taurine forms bile salts; gut bacteria form secondary bile acids via deconjugation/dehydroxylation.
Adrenal steroids: pregnenolone as common precursor; ACTH stimulates cholesterol desmolase (rate-limiting); downstream products include glucocorticoids, mineralocorticoids, and sex steroids.
Atherogenesis sequence: endothelial dysfunction $\rightarrow$ monocyte adhesion/transmigration $\rightarrow$ macrophage differentiation $\rightarrow$ oxidized LDL uptake $\rightarrow$ foam cell formation (fatty streak) $\rightarrow$ fibrous cap formation $\rightarrow$ plaque rupture $\rightarrow$ thrombosis.