Metabolism — General Whole-Body Metabolism of Carbohydrates, Proteins and Lipids
Metabolism is the sum of all chemical reactions that occur in living organisms to maintain life. In humans, whole-body metabolism integrates the biochemical pathways of carbohydrates, proteins and lipids in order to produce energy, provide precursors for biosynthesis, and maintain homeostasis across varying nutritional and physiological states. This article gives a comprehensive, exam-oriented overview of the principal pathways for each macronutrient, how they are integrated at the organ and hormonal level, key regulatory steps, and clinically important implications.
1. Basic concepts and the metabolic economy
At its simplest, metabolism can be divided into catabolism (breaking down molecules to release energy) and anabolism (building up molecules, consuming energy). Adenosine triphosphate (ATP) is the universal energy currency; reducing equivalents (NADH, FADH2) transfer electrons to oxidative phosphorylation to generate ATP. Metabolic pathways are spatially and temporally regulated: different tissues play specialized roles (e.g., liver in glucose buffering, muscle in movement and glycogen storage, adipose in fat storage, brain in constant glucose demand). Hormonal signals shift the balance between storage and mobilization according to nutrient availability, activity, stress and circadian rhythms.
2. Carbohydrate metabolism
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| Steps of Carbohydrates Metabolism |
2.1. Dietary carbohydrates — digestion and absorption
Dietary carbohydrates include starches (polysaccharides), disaccharides (sucrose, lactose) and monosaccharides (glucose, fructose, galactose). Digestion starts in the mouth (salivary α-amylase) and continues in the small intestine where pancreatic α-amylase breaks down starch to oligosaccharides and disaccharides. Brush border enzymes (maltase, sucrase, lactase, isomaltase) produce monosaccharides that are absorbed across enterocytes: glucose and galactose via sodium-dependent glucose transporters (SGLT1) and facilitated diffusion (GLUT2), fructose via GLUT5 and GLUT2.
2.2. Glycolysis and ATP production
Glycolysis is the cytosolic sequence that converts one glucose molecule into two molecules of pyruvate, generating a net gain of 2 ATP and 2 NADH per glucose. Key regulatory enzymes include hexokinase/glucokinase (glucose → glucose-6-phosphate), phosphofructokinase-1 (PFK-1, committing step controlled by energy status and allosteric effectors), and pyruvate kinase (PEP → pyruvate). Under aerobic conditions, pyruvate is transported into mitochondria and converted by pyruvate dehydrogenase (PDH) into acetyl-CoA, which enters the tricarboxylic acid (TCA) cycle. Under anaerobic conditions, pyruvate is reduced to lactate (by lactate dehydrogenase) to regenerate NAD⁺ for continued glycolytic flux.
2.3. TCA cycle and oxidative phosphorylation
The TCA cycle (Krebs cycle) in the mitochondrial matrix oxidizes acetyl-CoA to CO₂ while producing NADH and FADH₂. These reducing equivalents feed the electron transport chain, driving ATP synthesis through oxidative phosphorylation. The TCA cycle is amphibolic — it supplies precursors for biosynthesis (amino acids, gluconeogenic intermediates) as well as energy.
2.4. Glycogen metabolism: synthesis and breakdown
Glycogen is the storage form of glucose in animals, primarily located in liver (for blood glucose buffering) and muscle (for local energy during contraction). Glycogen synthesis (glycogenesis) uses glycogen synthase (adds glucose residues from UDP-glucose) and branching enzyme; glycogen breakdown (glycogenolysis) uses glycogen phosphorylase and debranching enzyme to release glucose-1-phosphate (converted to glucose-6-phosphate). Liver contains glucose-6-phosphatase to release free glucose into blood; muscle lacks this enzyme and thereby retains glucose for glycolysis.
2.5. Gluconeogenesis
Gluconeogenesis synthesizes glucose de novo from non-carbohydrate precursors (lactate, glycerol, glucogenic amino acids like alanine). Occurring mainly in liver and to some extent in kidney cortex, gluconeogenesis bypasses irreversible glycolytic steps using specific enzymes: pyruvate carboxylase (pyruvate → oxaloacetate), PEP carboxykinase (oxaloacetate → PEP), fructose-1,6-bisphosphatase, and glucose-6-phosphatase. Gluconeogenesis is upregulated during fasting and stress to maintain blood glucose for the brain and red blood cells.
2.6. Pentose phosphate pathway (hexose monophosphate shunt)
The pentose phosphate pathway (PPP) operates in the cytosol to generate NADPH (for reductive biosynthesis and antioxidant defense) and ribose-5-phosphate (for nucleotide synthesis). The oxidative phase produces NADPH and ribulose-5-phosphate; the non-oxidative phase interconverts sugars to feed glycolysis or nucleotide synthesis. Tissues with high NADPH demand (adipose, liver, red blood cells) use PPP extensively.
2.7. Regulation of carbohydrate metabolism
Key regulatory points balance carbohydrate flux according to needs:
- Hormonal control: Insulin promotes glucose uptake and glycogen synthesis; glucagon and catecholamines stimulate glycogenolysis and gluconeogenesis.
- Allosteric control: PFK-1 is activated by AMP and fructose-2,6-bisphosphate and inhibited by ATP and citrate; pyruvate kinase is activated by fructose-1,6-bisphosphate.
- Substrate availability and compartmentation: cytosolic NAD⁺/NADH ratio, ATP/ADP, and acetyl-CoA levels modulate enzyme activities (e.g., high acetyl-CoA stimulates pyruvate carboxylase for gluconeogenesis).
3. Protein (amino acid) metabolism
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| Steps of Protein Metabolism |
3.1. Dietary proteins — digestion and amino acid pool
Dietary proteins are hydrolysed to peptides and amino acids by gastric pepsin and pancreatic proteases (trypsin, chymotrypsin, elastase, carboxypeptidases) followed by brush border peptidases. Amino acids enter the circulating free amino acid pool — a dynamic reservoir used for protein synthesis, synthesis of nitrogen-containing compounds (neurotransmitters, porphyrins, nucleotides), and as metabolic fuels.
3.2. Transamination and deamination
Amino acids are metabolized primarily through removal of the amino group. Transamination transfers the α-amino group to α-ketoglutarate forming glutamate (catalyzed by aminotransferases; e.g., ALT, AST). Oxidative deamination of glutamate by glutamate dehydrogenase releases free ammonium (NH₄⁺) and regenerates α-ketoglutarate. This ammonium is toxic and must be detoxified by the urea cycle in the liver.
3.3. Urea cycle
The urea cycle converts toxic ammonia to urea for renal excretion. Key steps occur in both mitochondria and cytosol of hepatocytes: carbamoyl phosphate synthetase I (CPS I) combines NH₄⁺ with bicarbonate (activated by N-acetylglutamate), ornithine transcarbamoylase forms citrulline, and subsequent cytosolic enzymes (argininosuccinate synthetase, argininosuccinate lyase, arginase) produce urea and regenerate ornithine. Disorders of urea cycle enzymes cause hyperammonemia with neurological consequences.
3.4. Amino acids as metabolic fuels and precursors
Amino acids are classified as glucogenic (can yield gluconeogenic intermediates like pyruvate or TCA cycle intermediates) or ketogenic (yield acetyl-CoA or acetoacetyl-CoA, e.g., leucine, lysine). During fasting, protein catabolism supplies amino acids for gluconeogenesis (e.g., alanine cycle) and for ketone body synthesis indirectly. Amino acids also provide carbon skeletons for lipid synthesis and maintain TCA cycle anaplerosis.
3.5. Protein turnover and regulation
Protein synthesis and degradation are tightly controlled. Ubiquitin-proteasome pathway degrades short-lived regulatory proteins; lysosomal autophagy degrades bulk proteins and organelles during starvation. Hormones modulate turnover: insulin stimulates protein synthesis and inhibits proteolysis; glucocorticoids and glucagon promote proteolysis. Muscle protein balance determines lean body mass and influences metabolic rate.
3.6. Clinical considerations
Disorders of protein metabolism include inborn errors of amino acid catabolism (e.g., phenylketonuria), liver disease causing impaired urea synthesis and hyperammonemia, and catabolic states leading to muscle wasting (cachexia, prolonged fasting, uncontrolled diabetes). Measurement of nitrogen balance and plasma amino acids assists clinical assessment.
4. Lipid metabolism
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| Steps of Lipid Metabolism |
4.1. Dietary lipids — digestion, absorption and transport
Dietary lipids are mainly triglycerides, phospholipids and cholesterol esters. Emulsification by bile salts in the duodenum enables pancreatic lipase and colipase to hydrolyse triglycerides into monoacylglycerol and free fatty acids. These form mixed micelles that are absorbed by enterocytes, re-esterified into triglycerides, and packaged into chylomicrons — large lipoprotein particles that enter lymphatics and then systemic circulation. Chylomicrons deliver dietary triglycerides to peripheral tissues and remnants return to the liver.
4.2. Lipoproteins and their functions
Lipid transport in plasma is mediated by lipoproteins: chylomicrons (dietary TG transport), VLDL (hepatic TG export), IDL/LDL (cholesterol transport), HDL (reverse cholesterol transport). Lipoprotein lipase (LPL) on capillary endothelium hydrolyses TG in chylomicrons and VLDL releasing free fatty acids for uptake by muscle and adipose. Hepatic lipase and receptors (LDL receptor, scavenger receptors) manage lipoprotein clearance and cholesterol homeostasis.
4.3. Fatty acid activation and mitochondrial transport
Free fatty acids in the cytosol are activated to fatty acyl-CoA by acyl-CoA synthetase. Long-chain acyl-CoA cannot cross the inner mitochondrial membrane directly; the carnitine shuttle (carnitine palmitoyltransferase I and II, CPT I/II) transfers acyl groups into the mitochondrial matrix where β-oxidation occurs. Malonyl-CoA, the first intermediate in fatty acid synthesis, inhibits CPT I to prevent simultaneous fatty acid oxidation and synthesis.
4.4. β-Oxidation and energy yield
β-Oxidation sequentially removes two-carbon acetyl-CoA units from the carboxyl end of fatty acyl-CoA, producing FADH₂ and NADH per cycle that feed oxidative phosphorylation. Acetyl-CoA produced enters the TCA cycle (unless carbohydrate is scarce), generating large amounts of ATP. Fatty acids therefore provide dense energy per gram compared to carbohydrates or proteins.
4.5. Ketogenesis and ketone bodies
During prolonged fasting or uncontrolled diabetes when carbohydrate availability or insulin action is low, excess acetyl-CoA generated from β-oxidation is converted in hepatic mitochondria to ketone bodies (acetoacetate, β-hydroxybutyrate, and acetone). Ketone bodies are exported and used by the brain, heart and muscle as alternative fuels. Excessive ketone production leads to metabolic acidosis (ketoacidosis).
4.6. Fatty acid and triglyceride synthesis (lipogenesis)
Lipogenesis occurs mainly in liver and adipose tissue. Citrate exported from mitochondria supplies cytosolic acetyl-CoA; acetyl-CoA carboxylase (ACC) converts acetyl-CoA to malonyl-CoA (committed step), and fatty acid synthase elongates chains. NADPH (from PPP and malic enzyme) provides reducing power. Triglycerides are formed by esterification of glycerol-3-phosphate with fatty acyl-CoAs and stored in adipose.
4.7. Cholesterol metabolism
Cholesterol is synthesized de novo (in liver and other tissues) from acetyl-CoA through HMG-CoA reductase (rate-limiting enzyme, target of statins). Cholesterol is essential for membrane structure, steroid hormones and bile salts. Excess cholesterol is transported back to liver by HDL for excretion. Dysregulation causes atherosclerosis and cardiovascular disease.
4.8. Regulation of lipid metabolism
Lipid metabolism is hormonally regulated:
- Insulin stimulates lipogenesis and inhibits lipolysis (activates LPL, inhibits hormone-sensitive lipase).
- Glucagon and catecholamines activate lipolysis via increased cAMP and hormone-sensitive lipase activity in adipocytes.
- Malonyl-CoA inhibits CPT I to coordinate synthesis and oxidation.
- Transcriptional regulators (SREBP, PPARs) adjust enzyme expression for long-term control.
5. Integration of carbohydrate, protein and lipid metabolism
Metabolic pathways are highly interlinked; intermediates shuttle between pathways depending on energy and biosynthetic demands. Important integrative concepts include:
- Acetyl-CoA as a central node: formed from pyruvate (carbohydrates), fatty acid oxidation, and ketogenic amino acids; feeds TCA cycle or ketogenesis.
- Glycerol backbone: derived from glycolytic intermediate (dihydroxyacetone phosphate) linking carbohydrate and lipid metabolism for triglyceride synthesis.
- Glucose–alanine cycle: during prolonged exercise or fasting, muscle converts pyruvate to alanine (transamination), which is transported to liver for gluconeogenesis — nitrogen is returned via urea cycle.
- NADPH & reducing power: provided by PPP and malic enzyme for fatty acid and cholesterol synthesis; antioxidant defense depends on NADPH which ties carbohydrate flux to lipid anabolism and redox balance.
6. Hormonal regulation and the fed–fasting transition
Hormones coordinate whole-body substrate partitioning:
- Fed state (high insulin): glucose uptake and glycogen synthesis in liver and muscle; lipogenesis in liver and adipose; protein synthesis in muscle. Insulin suppresses gluconeogenesis, glycogenolysis, and lipolysis.
- Early fasting (post-absorptive): falling insulin and rising glucagon promote hepatic glycogenolysis to maintain blood glucose. Lipolysis begins releasing free fatty acids.
- Prolonged fasting: gluconeogenesis from amino acids and glycerol predominates; ketogenesis increases to provide alternative fuels for brain; muscle protein catabolism supplies substrates.
- Stress response: catecholamines, cortisol and growth hormone mobilize energy stores (glycogenolysis, gluconeogenesis, lipolysis) and decrease insulin action to prioritize immediate energy supply.
7. Organ roles and substrate fate
Different organs have specialized metabolic functions that together maintain systemic homeostasis:
- Liver: central metabolic organ — glycogen storage and release, gluconeogenesis, lipogenesis, ketogenesis, urea cycle, cholesterol synthesis and lipoprotein secretion.
- Muscle: major site for glucose uptake during activity (GLUT4), glycogen storage, fatty acid oxidation during prolonged exercise, and amino acid utilization for energy in severe fasting.
- Adipose tissue: energy storage as triglycerides, regulated lipolysis, endocrine function through adipokines influencing insulin sensitivity and inflammation.
- Brain: reliant on glucose (or ketone bodies during prolonged fasting) — lacks capacity for fatty acid oxidation, thus bloodstream glucose must be tightly maintained.
- Kidney: contributes to gluconeogenesis and ammonia metabolism; in prolonged fasting, renal gluconeogenesis becomes more important.
8. Clinical correlations and metabolic disorders
Disturbances in whole-body metabolism underlie many common diseases:
- Diabetes mellitus: absolute or relative insulin deficiency causes hyperglycemia, dyslipidemia, protein catabolism and long-term microvascular and macrovascular complications.
- Metabolic syndrome: central obesity, insulin resistance, dyslipidemia and hypertension increase cardiovascular risk.
- Fatty liver (NAFLD): excess hepatic triglyceride accumulation due to overeating, insulin resistance and altered lipid flux.
- Inherited metabolic disorders: defects in carbohydrate (glycogen storage diseases), amino acid (maple syrup urine disease, phenylketonuria) and lipid metabolism (lipid storage diseases) cause multisystem disease with specific biochemical fingerprints.
- Ketosis and ketoacidosis: physiologic ketosis during fasting vs pathologic diabetic ketoacidosis with dangerous acidosis and dehydration.
9. Nutritional and therapeutic implications
Understanding whole-body metabolism guides dietary recommendations and medical therapies. Balanced macronutrient intake supports energy needs and prevents excessive fluxes that lead to insulin resistance. Pharmacological interventions target metabolic enzymes and hormonal axes (e.g., metformin to reduce hepatic gluconeogenesis, statins to inhibit HMG-CoA reductase, GLP-1 receptor agonists to improve glycemic control and weight). Lifestyle measures (caloric restriction, exercise) remain cornerstone interventions to improve insulin sensitivity and modify lipid handling.
In conclusion, whole-body metabolism is a coordinated network in which carbohydrates, proteins and lipids continually exchange roles as fuel and precursors according to physiological demands. Mastery of the biochemical pathways, regulatory logic and organ specialization provides the framework to understand health, disease and therapeutic interventions that affect metabolic balance.
References and further reading (suggested)
- Lehninger Principles of Biochemistry — for detailed pathway mechanisms and regulation.
- Harper's Illustrated Biochemistry — concise, clinically oriented presentations.
- Clinical Biochemistry textbooks — for laboratory correlations and disease associations.
- Recent review articles on metabolic syndrome, insulin resistance and hepatic metabolism for updated clinical perspectives.
