Lipid Digestion, Transport, and Metabolism

Lipids: Structure, Roles, and Energy

Lipids are a heterogeneous group of compounds that include fats, oils, steroids, waxes, and related substances. They are related more by their physical properties than by a single chemical class: they are relatively insoluble in water and soluble in nonpolar solvents such as ether and chloroform. This group serves as excellent energy reserves, contribute to the structure of cell membranes, provide padding and thermal insulation, supply essential fatty acids (EFA), participate in hormone synthesis, and facilitate absorption of fat-soluble vitamins. Dietary lipids are predominantly triglycerides (about 95%), with the remainder comprising phospholipids, cholesterol esters, free cholesterol, and fat-soluble vitamins (FSV). Lipids can be synthesized and mobilized through complex processes that involve digestion, transport in the bloodstream, storage in adipose tissue, and utilization in various tissues. In vertebrates, fats are obtained from the diet, mobilized from stores in adipose tissue, and in the liver excess dietary carbohydrates can be converted to fats for export to other tissues.

Sources of Fatty Acids and Early Pathways

Cells obtain fatty acids from three primary sources: (i) fats consumed in the diet, (ii) fats stored in cells as lipid droplets (adipocytes), and (iii) fats synthesized in one organ for export to another. Different species rely on these sources to varying extents. In vertebrates, fats enter the diet, adipose tissue mobilizes stored fats, and the liver can convert excess dietary carbohydrates into fats for export to other tissues.

Examples of Fat Accumulation Strategies in Animals

Many species regularly accumulate substantial fat in anticipation of food scarcity. Examples include hibernators (grizzly bears, bats, fat-tailed dwarf lemurs, arctic ground squirrels), diapause (mosquitoes), migrators (salmon, bar-tailed godwit, monarch butterfly), and cave-dwellers or estivators (cavefish, olm, lungfish, snails). The Fat-tailed Dwarf Lemur's fat stores are well-documented in photography under a CC-BY 2.0 license.

Lipids as an Energy Reserve and Their Functional Roles

Eukaryotic organisms store most metabolic energy in lipids as long-term reserves; carbohydrates and proteins serve as short-term energy reserves. Lipids are energy-dense, yielding the greatest energy per unit weight and contributing significantly to energy homeostasis, thermoregulation, and membrane fluidity.

Lipid Storage Locations

Fat storage varies within and between species. Most mammals store fat intra-abdominally (visceral fat) or in peripheral adipose tissue (subcutaneous fat). Other organisms store lipids in distinct locations (e.g., feet in amphibians, tails in reptiles, heads in whales, fat bodies in insects). While adipose tissue is the primary lipid reservoir, other organs such as the liver, skeletal muscle, and pancreas can sequester and store lipids to be mobilized for rapid use.

Lipid Digestion and Emulsification: Why Lipids Need Special Handling

Lipid digestion presents challenges because triglycerides are large and not water-soluble, leading them to cluster in droplets within the watery digestive environment. The digestive system emulsifies fats to increase surface area and then enzymatically digests them with lipases. The mouth and stomach contribute modestly to digestion; the majority occurs in the small intestine. Emulsification is accomplished by bile salts, which are amphipathic detergents synthesized from cholesterol in the liver and stored in the gallbladder. They form mixed micelles with triacylglycerols, enabling lipases to access and hydrolyze fats. The enzymatic products—monoglycerides, free fatty acids, and glycerol—diffuse into intestinal mucosa, where they are reassembled into triglycerides and packaged into lipoprotein aggregates called chylomicrons.

Processing of Dietary Lipids in Vertebrates

Dietary triglycerides are first emulsified by bile salts and then hydrolyzed by pancreatic lipase into monoglycerides and free fatty acids. These products are taken up by enterocytes and reesterified into triglycerides, which are packaged with cholesterol and apolipoproteins into chylomicrons. Chylomicrons are released into the lymphatic system and then the bloodstream, delivering triglycerides to tissues such as muscle and adipose tissue. In the capillaries of these tissues, lipoprotein lipase (LPL), activated by apoC-II, hydrolyzes triglycerides to fatty acids and glycerol, which enter cells for oxidation or storage. Chylomicron remnants travel to the liver for further processing.

Enterohepatic Circulation and Micelle Formation

Before absorption, ingested triglycerides are converted from insoluble macroscopic fat particles to dispersed micelles by bile salts (e.g., taurocholic acid). Micelle formation increases the fraction of lipid accessible to water-soluble lipases. Lipase action breaks triglycerides down to monoacylglycerols, fatty acids, and glycerol, which diffuse into intestinal mucosa and are reassembled into triglycerides, packaged into chylomicrons, and transported via lymphatics to the blood. Bile salts are recycled through enterohepatic circulation to continue emulsification with new meals.

Processing of Dietary Lipids in Vertebrates: Detailed Pathway

Within the enterocytes, absorbed monoglycerides and fatty acids are reassembled into triglycerides and packaged into chylomicrons, which contain apolipoproteins. The chylomicrons enter the lymphatic system first, then the bloodstream, and are delivered to tissues such as muscle and adipose tissue. In capillaries, lipoprotein lipase hydrolyzes the triglycerides in chylomicrons to fatty acids and glycerol, which are taken up by cells for energy production or re-esterification and storage as triglycerides. The chylomicron remnants are taken up by the liver, completing the cycle. In the liver, triglycerides can be oxidized for energy or converted into ketone body precursors. When dietary fats exceed immediate needs, the liver packages triglycerides into VLDL, which transport triglycerides to adipose tissue for storage.

Lipoproteins: Surface and Core Architecture

Lipoproteins have a lipid core containing triglycerides and cholesterol esters, surrounded by a water-soluble surface coat comprised of apolipoproteins, phospholipids, and unesterified cholesterol. Chylomicrons, VLDL, IDL, LDL, and HDL vary in composition and density. The surface phospholipids display their hydrophilic heads outward and hydrophobic tails inward, with apolipoproteins providing amphipathic properties that facilitate lipid transport in blood.

Chylomicrons: Transporters from the Intestine to Tissues

Chylomicrons deliver triglycerides from digested food to tissues where they are used for energy or stored. Lipoprotein lipase, located on the endothelium of blood vessels, hydrolyzes triglycerides to fatty acids and glycerol, enabling tissue uptake. As triglycerides are removed, chylomicron size decreases, producing chylomicron remnants that return to the liver for processing. Surface apolipoproteins such as B-48, C-II, and C-III regulate uptake and metabolism of chylomicron contents.

Lipid Transport: From Liver to Tissues via VLDL and LDL

VLDL carries triglycerides synthesized in the liver and released into the bloodstream. Lipoprotein lipase hydrolyzes these triglycerides, enabling tissue uptake. As triglycerides are removed, VLDL becomes IDL and then LDL, which predominantly deliver cholesterol to body cells. HDL particles, rich in protein, scavenge cholesterol from cells and return it to the liver for disposal. The balance between these lipoprotein fractions constitutes the lipid profile used in clinical assessment.

Fatty Acid Uptake and Transport in Blood

Free fatty acids (FFA) released from adipose tissue lipolysis are bound to serum albumin for transport in the plasma. In postabsorptive states, plasma FFA levels range roughly from 10 to 30 mg/dL, largely as albumin-FFA complexes. FFAs dissociate from albumin at the plasma membrane and bind to fatty acid transport proteins that aid entry into cells, where intracellular fatty acid-binding proteins (FABPs) facilitate cytosolic trafficking.

Mobilization of Fat from Adipose Tissue

Triacylglycerols stored in adipose tissue are mobilized by hormone-sensitive triacylglycerol lipase (also called hormone-sensitive lipase). Hormones such as epinephrine and glucagon activate adenylyl cyclase, increasing cAMP, which activates protein kinase A (PKA). PKA phosphorylates perilipin and hormone-sensitive lipase, enabling lipolysis to proceed at the lipid droplet surface. Fatty acids released into the blood bind to albumin and are transported to tissues for oxidation, while glycerol is released and travels to the liver. In adipose tissue, glycerol kinase is absent, so glycerol is not phosphorylated there; it is transported to the liver where it is activated to glycerol-3-phosphate and can re-enter glycolysis or glycerolipid synthesis.

Glycerol Metabolism and Glycolytic Connection

The glycerol released from lipolysis is taken up by the liver, where it is phosphorylated by glycerol kinase to glycerol-3-phosphate. Glycerol-3-phosphate is then converted to dihydroxyacetone phosphate (DHAP) by glycerol-3-phosphate dehydrogenase, entering the glycolytic pathway. The glycerol moiety contributes only a small fraction of energy compared to fatty acids, because about 95% of the energy yield from TAGs resides in the fatty acids themselves; the glycerol moiety contributes roughly 5%.

Regulation of Fatty Acid Synthesis: De Novo Lipogenesis and Its Control

Fatty acid synthesis occurs in the cytosol, starting from acetyl-CoA which is generated in mitochondria but cannot cross the mitochondrial membrane. Acetyl-CoA is transported to the cytosol as citrate, which is cleaved back to acetyl-CoA and oxaloacetate by citrate lyase. Acetyl-CoA carboxylase (ACC) catalyzes the committed, rate-limiting step to form malonyl-CoA, the two-carbon donor for chain elongation. The fatty acid synthase (FAS) complex then performs a repeating four-step cycle (condensation, reduction, dehydration, and reduction) to elongate the growing acyl chain two carbons at a time, ultimately producing palmitate (16:0). The ACP (acyl carrier protein) within FAS carries growing acyl chains, with Cys-SH and Pan-SH arms providing functional docking points for acetyl and malonyl groups.

Regulation by Hormones and Nutritional State

Fatty acid synthesis is hormonally regulated. Insulin promotes fatty acid synthesis by activating ACC and supporting citrate supply, while glucagon and other hormones raise cAMP, activating protein kinase A and inhibiting ACC. Citrate acts as an allosteric activator of ACC and also suppresses phosphofructokinase-1, reducing glycolytic flux and thereby modulating acetyl-CoA availability. NADPH supplies reducing equivalents for the fatty acid synthase complex, largely derived from the pentose phosphate pathway (HMP shunt). Palmitoyl-CoA acts as a feedback inhibitor of ACC to prevent overproduction, and citrate serves as both a substrate and an activator for cytosolic acetyl-CoA formation.

Desaturation and Elongation of Fatty Acids

Humans desaturate fatty acids via desaturase enzymes, introducing cis double bonds, typically at Δ9. Mammals cannot introduce double bonds beyond Δ9; thus essential fatty acids such as linoleate (18:2 Δ9,12) and α-linolenate (18:3 Δ9,12,15) must be obtained from the diet. Desaturation and elongation systems in the smooth endoplasmic reticulum and mitochondria extend and modify fatty acids to produce longer-chain and polyunsaturated fatty acids used in membranes and signaling molecules.

Synthesis of TAG, Phospholipids, and Other Lipids

Liver and adipose tissue are the major sites of triacylglycerol (TAG) synthesis. In adipose tissue, TAGs are primarily stored; in liver, TAG synthesis largely supports export in VLDL particles. The fate of fatty acids—whether stored as TAG or incorporated into membrane phospholipids—depends on physiological needs: rapid growth requires membrane phospholipids, while surplus dietary or stored fatty acids favor storage as TAG. Glycerol-3-phosphate serves as the backbone for TAG and phospholipid assembly. In the liver, glycerol is activated by glycerol kinase; in adipose tissue, glycerol kinase is absent, so glycerol is primarily routed to liver metabolism.

Phospholipid Biosynthesis and Head-Group Formation

Membrane phospholipid synthesis occurs mainly on the endoplasmic reticulum and mitochondrial inner membranes. Glycerol-3-phosphate is acylated twice to form phosphatidic acid, which can be channeled via two routes to phosphatidic acid (either direct acylation or diacylglycerol phosphorylation). The head group is attached via a phosphodiester bond, with activation of one head-group hydroxyl by attachment of CDP (cytidine diphosphate) before head-group transfer. In eukaryotes, both CDP-diacylglycerol and CDP-activated head groups participate in phospholipid assembly.

Plasmalogens and Ether Lipids

Plasmalogens are ether lipids formed when an ether linkage replaces an ester linkage at the sn-1 position of glycerophospholipids, followed by head-group modification. The peroxisome is the primary site of plasmalogen synthesis. The characteristic vinyl ether linkage and subsequent desaturation steps create these lipids, which participate in membranes and signaling.

Sphingolipid Biosynthesis

Sphingolipid biosynthesis begins with serine and palmitoyl-CoA forming a long-chain base (sphinganine), which is acylated to form ceramide. Ceramide serves as a precursor to sphingomyelin and various glycosphingolipids such as cerebrosides. Sphingolipids play critical roles in membrane structure and cell signaling. Enzymes involved include mixed-function oxidases and various transferases that attach head groups to generate complex sphingolipids.

Degradation of Phospholipids and Sphingolipids

Phospholipases A1 and A2 hydrolyze fatty acids at the C1 and C2 positions, generating lysophospholipids and free fatty acids. Phospholipase C cleaves at the phosphate-glycerol bond, while phospholipase D cleaves the head group from phospholipids. Sphingomyelin degradation by sphingomyelinase yields ceramide and phosphocholine; ceramide can be further degraded to sphingosine and a free fatty acid. Defects in sphingolipid catabolism underlie certain lysosomal storage diseases such as Niemann-Pick and Farber’s disease.

Cholesterol Biosynthesis and Regulation

Cholesterol is essential for membranes, steroid hormone synthesis, and bile acids. It can be synthesized de novo in many animals, with hepatic cytosol and microsomes housing the cholesterol-synthesis enzymes. The pathway starts from acetyl-CoA and proceeds through HMG-CoA formation, HMG-CoA reductase, and mevalonate production, followed by activation to isoprenes (isopentenyl pyrophosphate and dimethylallyl pyrophosphate), then condensation to form squalene, and ultimately lanosterol and cholesterol through multiple steps. The rate-limiting step is the formation of mevalonate via HMG-CoA reductase, which is a key regulatory enzyme.

Mevalonate Pathway and Activated Isoprenes

Two acetyl-CoA molecules condense to form acetoacetyl-CoA, which then adds another acetyl-CoA to generate HMG-CoA. HMG-CoA reductase uses NADPH to reduce HMG-CoA to mevalonate, a committed step in cholesterol synthesis. Mevalonate is converted to activated isoprenes through a series of phosphorylation and decarboxylation steps, producing isopentenyl pyrophosphate and dimethylallyl pyrophosphate, the two activated isoprenes essential for isoprenoid and cholesterol biosynthesis.

Squalene and Sterol Nucleus Formation

Six activated isoprene units condense to form squalene, which then undergoes oxidation and cyclization to form the four-ring steroid nucleus. Lanosterol is the immediate precursor to cholesterol, which is produced after a series of rearrangements and removals of methyl groups and other modifications. In parallel, sterol synthesis and transport are tightly regulated by feedback mechanisms and hormonal signals.

Regulation of Cholesterol Synthesis

Cholesterol synthesis is subject to feedback control: higher cellular cholesterol downregulates HMG-CoA reductase transcription. Hormonal signals influence the activity of HMG-CoA reductase by altering its phosphorylation state. Glucagon and glucocorticoids promote the phosphorylated, inactive form, while insulin and thyroxine promote the dephosphorylated, active form. Drugs such as compactin and lovastatin (mevinolin) competitively inhibit HMG-CoA reductase, reducing cholesterol synthesis. Bile acids can also inhibit this enzyme, and fasting can reduce its activity. These regulatory mechanisms affect circulating cholesterol levels and lipid homeostasis.

Pharmacology and Therapeutics in Lipid Disorders

Several therapeutic strategies target lipid metabolism. HMG-CoA reductase inhibitors (statins) reduce hepatic cholesterol synthesis and upregulate LDL receptors, lowering plasma LDL. Other agents reduce VLDL secretion (e.g., certain fibrates) or interrupt intestinal cholesterol absorption (bile acid sequestrants). Nutritional and lifestyle factors such as exercise, dietary fat composition (particularly reducing saturated fats and incorporating polyunsaturated fatty acids), and fiber intake influence lipid profiles by altering lipoprotein metabolism and cholesterol handling in the liver and intestines.

Regulation and Availability of NADPH in Lipogenesis

NADPH provides the reducing equivalents for fatty acid synthesis. About 50–60% of required NADPH is supplied by the pentose phosphate pathway, with additional contributions from cytosolic reactions linked to citrate cleavage and the malic enzyme pathway. The availability of NADPH directly affects the rate of fatty acid synthesis.

Relationship Between Citrate, Acetyl-CoA, and Lipogenesis

The transport of acetyl-CoA from mitochondria to the cytosol involves citrate as a carrier. When mitochondrial acetyl-CoA and ATP are high, citrate is exported to the cytosol, where it is cleaved to produce acetyl-CoA and oxaloacetate. Citrate also serves as an allosteric activator of acetyl-CoA carboxylase and inhibits phosphofructokinase-1, thereby modulating glycolytic flux and fatty acid synthesis.

Long-Chain Saturated Fatty Acids: Elongation Pathways

Palmitate (16:0) is the principal product of lipogenesis and serves as the precursor for other long-chain fatty acids. Elongation to stearate (18:0) and longer chains occurs via microsomal elongation systems in the smooth endoplasmic reticulum using malonyl-CoA and NADPH, with separate elongation systems operating in mitochondria. These elongation pathways expand the repertoire of fatty acids incorporated into membranes and lipids.

Ketone Bodies: Formation, Utilization, and Clinical Relevance

Ketone bodies (acetoacetate, β-hydroxybutyrate, acetone) are produced in the liver when acetyl-CoA accumulates under conditions where carbohydrate supply is limited (e.g., fasting or diabetes). Acetoacetate is the primary ketone body, with β-hydroxybutyrate and acetone as secondary products. Ketone bodies are exported to extrahepatic tissues, where they are converted back to acetyl-CoA and oxidized in the TCA cycle for energy. The heart, skeletal muscle, and renal cortex readily utilize ketone bodies; brain and skeletal muscle can adapt to use them during prolonged fasting.

Ketogenesis: Pathways to Acetoacetate and Beyond

Ketone bodies originate from acetyl-CoA rather than from glucose. Acetoacetyl-CoA can be converted to acetoacetate via acetoacetyl-CoA deacylase, or via a pathway involving HMG-CoA formation and lyase activity. Two acetyl-CoA molecules condense to form acetoacetyl-CoA; subsequent reactions yield HMG-CoA and then acetoacetate or via alternative routes. Acetone is formed by spontaneous non-enzymatic decarboxylation of acetoacetate, while β-hydroxybutyrate is produced by the reduction of acetoacetate. These ketone bodies are released into the bloodstream and can be used as energy substrates by extrahepatic tissues.

Ketolysis and Ketone Body Utilization

In extrahepatic tissues, ketone bodies are activated to acetoacetyl-CoA and then split into two acetyl-CoA units that feed the TCA cycle. The major pathway involves acetoacetate reacting with succinyl-CoA, catalyzed by thiophorase (CoA transferase), to form acetoacetyl-CoA and succinate. Acetoacetyl-CoA is then cleaved to two acetyl-CoA molecules that enter the TCA cycle. Minor pathways include activation of acetoacetate by CoA via acetoacetyl-CoA synthetase.

Ketosis and Related Disorders

Ketosis is the accumulation of ketone bodies in blood when their production exceeds peripheral utilization. Ketone bodies are acidic, and accumulation can cause metabolic acidosis (ketoacidosis), dehydration, and electrolyte disturbances. Ketone bodies can be detected in urine using Rothera’s test (positive for acetone or acetoacetate, not β-hydroxybutyrate). Ketosis can result from diabetes mellitus, starvation, or dietary factors that promote ketogenesis. Conditions such as uncontrolled diabetes can cause severe ketosis due to excessive lipolysis and acetyl-CoA production that exceeds TCA cycle capacity. The condition can lead to dehydration, osmotic diuresis, and potentially coma if not treated.

Odd- and Even-Carbon Fatty Acids and Special Pathways

β-oxidation processes fatty acids with even or odd numbers of carbon atoms. For odd-chain fatty acids, the final β-oxidation cycle yields propionyl-CoA, which is converted to succinyl-CoA and enters the TCA cycle after carboxylation and mutase steps (requiring biotin and vitamin B12). Propionyl-CoA carboxylase converts propionyl-CoA to methylmalonyl-CoA, which is racemized and rearranged by methylmalonyl-CoA mutase (B12-dependent) to succinyl-CoA. Defects in this pathway can lead to methylmalonic acidemia, with metabolic acidosis and CNS damage.

Unsaturated Fatty Acids: Adjustments in β-Oxidation

Unsaturated fatty acids pose challenges because the standard β-oxidation pathway handles trans double bonds. The presence of cis double bonds can hinder enoyl-CoA hydratase activity. Two additional enzymes—an isomerase and an epimerase (reductase)—allow oxidation to proceed by converting cis bonds to trans and by repositioning double bonds so that β-oxidation can continue. Monounsaturated fatty acids (e.g., oleate, 18:1 Δ9) are processed with isomerase to yield trans-2-enoyl-CoA, which can be further processed by the remaining β-oxidation steps.

Peroxisomal β-Oxidation and Special Oxidation Pathways

Although mitochondrial β-oxidation is the major fatty acid degradation pathway, peroxisomes also oxidize fatty acids, particularly very-long-chain fatty acids. In peroxisomes, the first oxidative step transfers electrons directly to O2, producing H2O2, which is rapidly broken down by catalase. Peroxisomal oxidation yields heat rather than ATP and is upregulated by high-fat diets and certain hypolipidemic drugs. Peroxisomal metabolism is especially important for very-long-chain fatty acids, which are then shortened for transfer to mitochondria.

Alpha-Oxidation and Omega-Oxidation

Alpha-oxidation removes carbon atoms from the carboxyl end of branched fatty acids (e.g., phytanic acid) that block β-oxidation. It is important for the catabolism of branched-chain fatty acids and phytanic acid, which is derived from dietary phytols (chlorophyll). Omega-oxidation, located in the endoplasmic reticulum, is a minor pathway that becomes more important when β-oxidation is defective (e.g., carnitine deficiency). Omega-oxidation can contribute to fatty acid degradation under certain conditions.

Metabolic Water from Fat Oxidation

Fatty acid oxidation generates metabolic water, a significant adaptation in some animals. For example, oxidation of a single palmitic acid molecule yields water molecules that contribute to hydration in desert-dwelling species like camels, supporting long treks with reduced water intake. This metabolic water production is an additional benefit of fat oxidation beyond energy production and is often accompanied by reduced urinary water loss as an adaptation.

Ketone Bodies: Structure, Utilization, and Clinical Insights

Ketone bodies include acetoacetate, β-hydroxybutyrate, and acetone. Their formation and utilization involve a balance between production in the liver and utilization in extrahepatic tissues. In ketosis, increased ketone body production can lead to metabolic acidosis if not matched by utilization. Diagnosis may involve urine tests (Rothera’s test) and serum ethanol markers; the presence and proportions of each ketone body reflect metabolic state, dietary intake, and disease conditions.

Fatty Acid Synthesis: Key Enzymes and Complex Organization

Fatty acid synthesis requires a coordinated set of enzymes in the fatty acid synthase (FAS) complex, which contains ACP and multiple catalytic activities: acetyl-CoA-ACP transacetylase, β-ketoacyl-ACP synthase, malonyl-CoA-ACP transferase, β-ketoacyl-ACP reductase, β-hydroxyacyl-ACP dehydratase, and enoyl-ACP reductase. The synthesis proceeds through a repeating cycle that extends the carbon chain two carbons at a time, starting from an acetyl starter unit and ending when palmitate (C16:0) is released from the ACP. The overall process is efficient and self-contained within the FAS complex.

Summary of Core Concepts

• Lipids are hydrophobic energy-rich molecules essential for energy storage, membrane structure, insulation, hormone synthesis, and vitamin absorption. The major dietary lipids are triglycerides, with a small fraction of phospholipids, cholesterol esters, and free cholesterol.
• Digestion of dietary lipids relies on emulsification by bile salts, followed by pancreatic lipase action to produce monoacylglycerols and free fatty acids, which are absorbed by enterocytes and reassembled into triglycerides to form chylomicrons.
• Lipoproteins transport lipids in the bloodstream. Chylomicrons deliver dietary triglycerides to tissues; VLDL carries endogenous triglycerides from the liver; LDL delivers cholesterol to tissues; HDL scavenges cholesterol for return to the liver.
• Stored fat is mobilized by hormone-sensitive lipase under hormonal control (epinephrine, glucagon) via a cAMP-PKA pathway, leading to the release of free fatty acids and glycerol into the blood. Fatty acids are transported bound to albumin to tissues for oxidation; glycerol is transported to the liver and used in glycolysis or gluconeogenesis.
• Fatty acids are activated to Acyl-CoA, transported into mitochondria via the carnitine shuttle, and undergo β-oxidation to produce acetyl-CoA, FADH2, and NADH. The acetyl-CoA enters the TCA cycle; energy yield per palmitate is approximately $106 ext{ ATP}$ after accounting for activation and complete oxidation (8 acetyl-CoA → 80 ATP; 7 FADH2 → 10.5 ATP; 7 NADH → 17.5 ATP; minus 2 ATP for activation).
• Peroxisomal β-oxidation handles very-long-chain fatty acids and yields heat rather than ATP; alpha-oxidation and omega-oxidation extend the range of substrates that can be metabolized, especially branched-chain or very long-chain fatty acids.
• Unsaturated fatty acids require isomerases and reductases to reposition cis double bonds into substrates compatible with the β-oxidation enzymes; essential fatty acids (e.g., linoleate and linolenate) must be obtained from the diet because humans cannot introduce certain double bonds endogenously.
• Ketone bodies are produced in the liver under carbohydrate-restricted conditions and used by heart, muscle, and kidney as alternative energy sources. Ketosis and ketoacidosis are pathological states that require clinical attention.
• Fatty acid synthesis (de novo) occurs in the cytosol, driven by acetyl-CoA and NADPH, with citrate shuttling acetyl-CoA from mitochondria to the cytosol. Acetyl-CoA carboxylase converts acetyl-CoA to malonyl-CoA, and the fatty acid synthase complex elongates the chain to palmitate. Regulation is influenced by hormones, energy status, and substrate availability, with malonyl-CoA also inhibiting fatty acid entry into mitochondria by blocking CPT I.
• Cholesterol biosynthesis proceeds from acetyl-CoA through the mevalonate pathway, with HMG-CoA reductase as the rate-limiting enzyme and a suite of steps generating activated isoprenes and ultimately cholesterol. Cholesterol homeostasis is tightly regulated by feedback and hormonal signals; statins inhibit HMG-CoA reductase and reduce cholesterol synthesis.
• The biosynthesis of membrane phospholipids and sphingolipids arises from acetyl-CoA and glycerol backbones, involving complex enzymatic steps for attaching fatty acids and head groups, with peroxisomal steps contributing to plasmalogens and ether lipids.
• Lipid disorders include steatorrhea (malabsorption of fat), transport and metabolic disorders (e.g., MCAD deficiency), peroxisomal disorders (e.g., Zellweger syndrome), Niemann-Pick disease, and other conditions affecting lipid digestion, transport, and metabolism. Treatments may include dietary modifications, supplementation, and pharmacological interventions targeting enzymatic steps.

– End of notes –