Comprehensive Study Notes: Lipids, Cellular Structure & Signaling, Genetics, and Metabolism
Lipid Synthesis & Storage
Four major plasma lipoproteins (named by density; smallest to highest density) and the four major lipid classes they carry
Chylomicrons (not a true lipoprotein class for density labeling but included): carry dietary TAGs
Very Low Density Lipoproteins (VLDL): carry endogenous TAGs from liver to tissues
Intermediate Density Lipoproteins (IDL/VLDL remnants): remnants after TAG hydrolysis
Low Density Lipoproteins (LDL): deliver cholesterol to cells
High Density Lipoproteins (HDL): pick up cholesterol from tissues and deliver to liver (reverse transport)
Major apolipoproteins by lipoprotein class
Chylomicrons: apoB-48, apoC-II, apoE
VLDL: apoB-100, apoC-II, apoE
IDL: apoB-100, apoE
LDL: apoB-100
HDL: apoA-1, apoC-II, apoE; apoA-1 activates LCAT to produce cholesterol esters
Core structure and function of lipoproteins
Lipoproteins = fat bubbles with a phospholipid exterior and hollow interior that transports TAGs
Cholesterol in the phospholipid membrane helps fluidity while limiting permeability
TAGs stored in hollow interior for transport
Difference between chylomicrons and lipoproteins: TAG origin and apolipoproteins governing circulation
Roles of apolipoproteins and enzymes in lipoprotein metabolism
apoC-II activates Lipoprotein Lipase (LPL) on capillary endothelium; LPL hydrolyzes TAGs in chylomicrons and VLDLs
apoE is used for hepatic uptake of remnants (IDL, chylomicron remnants)
apoB-48: synthesized in intestine for chylomicrons; apoB-100: synthesized in liver for VLDL/LDL
ApoA-1 in HDL activates LCAT (lecithin–cholesterol acyltransferase) to convert cholesterol to cholesterol esters for HDL
Lipoprotein transport and the liver
Chylomicron route: dietary fats → lymphatics (lacteals) → bloodstream → tissues (adipose, muscle); remnants taken up by liver via apoB-48 interactions (apoE, apoC-II)
Chylomicron remnants and LDL receptor–mediated uptake contribute to hepatic cholesterol management
Liver roles: packages fatty acids into VLDL for export; performs endocytosis of chylomicrons via apoB-48; central regulator of lipid transport and metabolism
Lipid storage and utilization in tissues
Adipose tissue stores triacylglycerol (TAG); muscle tissue uses fatty acids for energy
Insulin regulates lipid storage by activating LPL in adipose tissue (and muscle) to hydrolyze TAGs in circulating lipoproteins for storage or energy
Lipoprotein lipase (LPL) activity and TAG hydrolysis
LPL sits on luminal surface of capillaries in adipose and muscle
Activated by apoC-II; hydrolyzes TAGs in circulating lipoproteins to free fatty acids (FFAs) for uptake and storage in adipose tissue or oxidation in muscle
Lipogenesis and TAG storage in the fed state
Insulin promotes fatty acid storage and lipogenesis; citrate exported to cytosol activates acetyl-CoA carboxylase to form malonyl-CoA
Acetyl-CoA carboxylase requires ATP, biotin, and CO2 to form malonyl-CoA
Fatty acid synthase elongates growing fatty acid by 2-carbon units; NADPH (from PPP) provides reducing equivalents
De novo fatty acid synthesis from acetyl-CoA
Transfer Acetyl-CoA from mitochondria to cytosol via citrate shuttle
Acetyl-CoA cannot cross mitochondrial membranes directly; citrate synthase forms citrate; citrate lyase cleaves citrate to OAA and acetyl-CoA
Acetyl-CoA → Malonyl-CoA (AC carboxylase) requires ATP, biotin, CO2
From malonyl-CoA, two-carbon units are added by fatty acid synthase; NADPH supplies reducing equivalents
Palmitate (C16:0) produced as the end product of de novo synthesis
Overall stoichiometry (palmitate synthesis):
Fatty liver diseases and apoB-100 dependence
Alcoholic fatty liver disease: ethanol inhibits VLDL transport from liver; fatty liver results from trapped VLDL and accumulated fatty acids
Nonalcoholic fatty liver disease (NAFLD): related to disruptions in apoB-100 and VLDL export; insulin resistance contributes to impaired lipoprotein processing
Triacylglycerol synthesis in liver and adipose tissue
TAGs are synthesized in liver by combining 3 fatty acids with glycerol-3-phosphate head
Glycerol-3-phosphate sources:
Phosphorylation of free glycerol via glycerol kinase
Reduction of DHAP via glycerol-3-phosphate dehydrogenase (adipose and liver)
Adipose tissue lacks glycerol kinase and relies on glucose uptake to generate DHAP for TAG synthesis
Cholesterol biosynthesis and regulation
Pathway overview 1) Acetyl-CoA + Acetoacetyl-CoA → HMG-CoA 2) HMG-CoA reduced by HMG-CoA reductase to mevalonate (rate-limiting step)
Denoted as the rate-limiting enzyme; inhibited by cholesterol, glucagon, and statins
3) Mevalonate → cholesterol through several steps
Key regulatory enzyme
HMG-CoA reductase (rate-limiting in cholesterol de novo synthesis)
Regulation and clinical relevance
Negative feedback by cholesterol; pharmacologic statins inhibit HMG-CoA reductase to lower cholesterol synthesis
Cytoskeleton & Extracellular Matrix (ECM)
Three major types of cytoskeletal filaments
Actin Filaments (microfilaments)
Polarity with barbed (+) and pointed (-) ends; subunits: G-actin (globular) and F-actin (filamentous)
Polymerization helpers:
Formin: nucleates and elongates, adds ATP-bound G-actin to barbed end
Profilin: promotes ATP binding on G-actin
Arp2/3: nucleates new branches and growth
Capping proteins: cap both ends to prevent depolymerization
Coflin: cleaves filament to create new ends for growth
Roles: contractile rings in cytokinesis; vesicular transport highways; microvilli structure (fimbrin, villin as bundling proteins)
Structures: pseudopodia, lamellipodia, filopodia
Microtubules
Composed of α- and β-tubulin dimers; form hollow tubes with minus end anchored at centrosome (γ-tubulin ring) and plus end outward
Microtubule-associated proteins (MAPs): polymerases and depolymerases
Motor proteins: kinesin (anterograde, toward plus end), dynein (retrograde, toward minus end)
Cilia & flagella: 9+2 microtubule structure; dynein drives bending motions
Intermediate Filaments
Dimer-based, tetramer assembly; form apolar filaments (twizzler-like)
Provide mechanical resilience and connect to desmosomes/hemidesmosomes
ECM components and their roles
Fibrous proteins: collagen (most abundant; triple helix with glycine every third residue; hydroxyproline contributes to scurvy), forms bone, tendon, basal lamina; basal lamina filters molecules
Glycosaminoglycans (GAGs) & Proteoglycans: repeating disaccharide units; proteoglycans bind core proteins; hyaluronan is a unique, non-sulfated GAG; proteoglycans form aggregates (aggrecan) and form a gel-like ECM
Adhesion proteins: fibronectin (binds proteoglycans to collagen; recognized by integrins), laminin (forms networks in basal laminae)
Diseases linked to ECM/cytoskeleton disruptions
Scurvy: vitamin C deficiency; impaired prolyl hydroxylase → weakened collagen; symptoms include gingival bleeding, skin lesions
Osteogenesis Imperfecta: COL1A1/COL1A2 mutations (type I collagen) → brittle bones
Ehlers-Danlos Syndrome: COL3A1 mutation (type III collagen) → hyperflexible skin, joints, tissue fragility
Marfan Syndrome: FBN1 mutation (fibrillin-1) → abnormal TGF-β signaling; arachnodactyly, lens dislocation, risk of aortic aneurysm/dissection
Loeys-Dietz Syndrome: mutations in TGFBR1/2 or SMAD3 → severe cardiovascular manifestations without lens subluxation
Deafness: GJB2 (connexin-26) mutations affecting gap junctions in the ear
Cell–ECM junctions and adhesion structures
Focal adhesions: actin–integrin connections via talin, vinculin, and α-actinin
Hemidesmosomes: intermediate filament–integrin connections to the basal lamina
Desmosomes: cadherin-based cell–cell junctions linked to intermediate filaments
Tight junctions (occludin, claudins): seal epithelial layers
Gap junctions: connexins forming channels for intercellular communication
Cell Membranes & Cellular Homeostasis
Membrane composition and properties
Phospholipids: amphipathic; hydrophilic head (choline, phosphate, glycerol) and hydrophobic tails (often cis double bonds for fluidity)
Phosphoglycerides, sphingolipids, and glycolipids (glycolipids face extracellular surface) comprise the membrane
Lipid rafts: microdomains rich in cholesterol, sphingolipids, and certain proteins; promote coordinated signaling
Gangliosides: glycolipids with sialic acids; Tay-Sachs disease due to HEXA frameshift mutation leading to accumulation of gangliosides in lysosomes
Cholesterol: modulates membrane rigidity and permeability
Membrane-associated proteins
Flippase: flips phospholipids across leaflets (rare, but contributes to asymmetry)
Lectins: proteins that bind carbohydrate sequences on cells (e.g., leukocytes, platelets, epithelial cells)
Membrane transport mechanisms
Carriers: undergo conformational changes; may be active or passive
Channels: can be constitutively open or ligand-gated; selective for ions/molecules
Endocytosis / Exocytosis
Phagocytosis, Caveolae-mediated endocytosis, Receptor-mediated endocytosis, Transcytosis
Aquaporins and ion channels: selective for substrates based on size and pore properties
Key transporter systems and clinical examples
CFTR: chloride channel; mutations cause cystic fibrosis (autosomal recessive) with hypertonic sweat and respiratory infections; CFTR modulates ENaC activity in epithelia
Cholera toxin: activates adenylyl cyclase via Gs, raises cAMP, opens CFTR → Cl− and water secretion into intestinal lumen (secretory diarrhea)
Na+/K+ ATPase: basolateral pump maintaining gradients (example in gastric parietal cells for acid secretion)
Omeprazole: inhibits H+/K+-ATPase (gastric acid secretion)
Receptors and signaling architectures
Receptors: extracellular ligand binding triggers intracellular signaling
Intracellular signaling often begins with receptor activation and propagates via second messengers or kinase cascades
Receptors & Cell Signaling
General signaling framework
1) Signaling cell emits ligand; receiver cell must have compatible receptor
2) Receptor activation triggers intracellular signaling cascades
3) Signaling cascades alter effector proteins and cell behaviorCategories of extracellular signaling and receptor types
Intracellular signals: hydrophobic molecules (steroids, NO) can diffuse through membranes and bind intracellular receptors (nuclear receptors) to modulate transcription
Extracellular signals: hydrophilic or large molecules (peptides, growth factors, prostaglandins, neurotransmitters) often bind surface receptors
Peptide hormones vs neuropeptides vs growth factors
Neurotransmitters act at ligand-gated ion channels or GPCRs
Eicosanoids (e.g., prostaglandins) bind cell-surface receptors
Key receptor families and pathways
Ion-channel coupled receptors (ionotropic): ligand-gated ion channels regulate ionic flow and neuronal signaling
G protein-coupled receptors (GPCRs): 7-transmembrane domain receptors; signal via G proteins (Gs, Gi, Gq)
Gs: activates adenylyl cyclase → ↑cAMP
Gi: inhibits adenylyl cyclase ↓cAMP
Gq: activates phospholipase C → IP3 and DAG; IP3 raises intracellular Ca2+, DAG activates protein kinase C (PKC)
Receptor tyrosine kinases (RTKs): ligand-induced dimerization and trans-phosphorylation; downstream pathways include Ras–Raf–MEK–ERK
Tyrosine kinase–associated receptors: JAK/STAT signaling
Receptor guanylyl cyclases: produce cGMP as second messenger
Serine/threonine kinase receptors: TGF-β signaling via SMAD transcription factors
Notch signaling: proteolytic cleavage releases intracellular domain that acts as transcription factor in nucleus
Wnt/Frizzled signaling: β-catenin stabilization and transcriptional activation
Hedgehog/Patched-Smoothened: Hedgehog ligand relieves Patched inhibition; Smoothened promotes transcription
SHH, FGFs, BMPs, Nodal and related players in development
Notable downstream pathways and second messengers
cAMP: formed by adenylyl cyclase; degraded by phosphodiesterases; activates PKA
cGMP: formed by guanylyl cyclase; degrades by phosphodiesterases; activates PKG, ion channels
IP3/DAG: PLC cleaves PIP2 to generate IP3 (Ca2+ mobilization) and DAG (PKC activation)
MAPK cascade: Ras → Raf → MEK → ERK; drives cell growth and differentiation
JAK/STAT: cytokine receptors activate JAK; STATs translocate to nucleus to drive transcription
TGF-β/SMAD: serine/threonine kinase receptors phosphorylate SMADs; SMADs regulate transcription
NF-κB: resting IκB inhibits NF-κB; stimuli activate IκB kinase → degradation of IκB → NF-κB translocates to nucleus
Integrins and signaling
Integrins link ECM to cytoskeleton in focal adhesions and can initiate signaling via focal adhesion kinase (FAK) autophosphorylation
Death receptors and apoptosis
Fas receptor family (death receptors) cluster cytosolic death domains to trigger intrinsic apoptosis or inflammatory signaling
Lipid Mobilization, Catabolism & Ketone Bodies
Fatty acid mobilization and transport
Lipolysis in adipose tissue liberates FFAs and glycerol from TAGs via hormone sensitive lipase (HSL) activation by glucagon/epinephrine
FFAs bind albumin in blood for transport to tissues
Mitochondrial entry of fatty acids for beta-oxidation
Activation: fatty acids are converted to fatty acyl-CoA by acyl-CoA synthetase (acyl-CoA formation requires ATP)
Outer mitochondrial membrane: carnitine palmitoyltransferase I (CPT I) transfers the fatty acyl group to carnitine
Inner mitochondrial membrane: CPT II transfers the fatty acyl group back to CoA inside matrix
Beta-oxidation in mitochondria yields acetyl-CoA, FADH2, and NADH; acetyl-CoA enters TCA or ketogenesis depending on metabolic state
Beta-oxidation yield (palmitate, C16:0)
Beta-oxidation cycles yield 7 FADH2, 7 NADH, and 8 acetyl-CoA per palmitate
Per palmitate, total ATP yield is given as:
In this material, the total yield is stated as 129 ATP per palmitate
Carnitine role and disorders
Carnitine shuttles long-chain fatty acids into mitochondria
Deficiencies: CPT II deficiency (myopathic symptoms, brown urine), carnitine deficiency (muscle pain, high triglycerides)
Peroxisomal defects (Zellweger syndrome) affect VLCFA metabolism; phytanic acid accumulation with Phyh deficiency
Peroxisomal transport and VLCFA metabolism
VLCFAs require peroxisomes for β-oxidation; defects disrupt metabolism
Ketone bodies and ketogenesis
Ketone bodies: acetone, 3-hydroxybutyrate, acetoacetate
Ketogenesis in liver mitochondria: HMG-CoA synthase and HMG-CoA lyase generate ketone bodies
Rate-limiting step: HMG-CoA synthase (in ketogenesis)
Ketone bodies serve as fuels for extrahepatic tissues during fasting or carbohydrate deprivation; brain and muscle can utilize ketones; liver and RBCs cannot use ketone bodies (liver lacks thiophorase; RBCs lack mitochondria)
Ketosis and ketoacidosis can occur in alcohol abuse, Type I diabetes, prolonged fasting, and some children; acetone imparts fruity breath
Fatty Liver Disease, Metabolism & Regulation
Alcoholic fatty liver disease
Ethanol inhibits VLDL export from liver; cholesterol synthesis and palmitate production continue, but VLDL cannot leave the liver
Nonalcoholic fatty liver disease (NAFLD)
Often linked to apoB-100 transport defects and hepatic lipid accumulation; insulin resistance contributes to NAFLD progression
Regulation of hepatic VLDL secretion by diet & hormones
Fed state: insulin promotes lipogenesis; insulin also activates LPL to process circulating lipoproteins
LPL action on VLDL and chylomicrons hydrolyzes TAGs to FFAs for storage or energy
Cholesterol Biosynthesis & Regulation (Expanded)
Pathway overview
Acetyl-CoA + Acetoacetyl-CoA → HMG-CoA
HMG-CoA reductase reduces HMG-CoA to mevalonate (rate-limiting step)
Mevalonate → cholesterol through downstream steps
Regulation of HMG-CoA reductase
Inhibited by cholesterol via negative feedback, by glucagon, and by statins
Activation stimulates cholesterol synthesis; regulation matches cellular cholesterol needs
Hormones, Signaling & Genomic Regulation
Hormone types and hydrophilicity/hydrophobicity
Hydrophilic hormones (e.g., peptide hormones, catecholamines): stored in vesicles; short-to-intermediate half-lives; act on surface receptors
Hydrophobic hormones (steroids, thyroid hormones): diffuse through membranes; long half-lives; often bind to intracellular receptors (nuclear receptor family), regulating gene transcription
Four signal transduction pathways for hydrophilic hormones
Integrin-mediated signaling (growth signals)
Ligand-gated ion channels (neurohormones)
Receptor tyrosine kinases / receptor enzymes (example: leptin via JAK/STAT)
GPCRs (adenylyl cyclase–cAMP, PKC–Ca2+ pathways)
Nuclear receptors for hydrophobic signals
Ligand binding leads to receptor activation, dimerization, nuclear translocation, and transcriptional regulation
Hormone signaling regulation concepts
Up-regulation vs down-regulation: receptor density changes with hormone levels to maintain homeostasis
Negative and positive feedback in hormonal systems
Hormone half-life and pharmacodynamics
Hormone signaling in pharmacology
Agonists vs antagonists; receptor modulation; therapeutic targeting
Types of hormone interactions and signaling networks
NOTCH, WNT/β-catenin, Hedgehog (Patched/Smoothened), SHH, Nodal
TGF-β/SMAD signaling; JAK/STAT; RTKs; GPCRs; NF-κB pathways
Second messengers and their synthesis/degradation
cAMP: ATP → cAMP via adenylyl cyclase; degraded by phosphodiesterases; acts on PKA
cGMP: GTP → cGMP via guanylyl cyclase; degraded to GMP by phosphodiesterases; activates PKG and other targets
IP3 and DAG: PLC cleaves PIP2 to IP3 (Ca2+ mobilization) and DAG (PKC activation)
Amino Acid Metabolism & Nitrogen Handling
Aminotransferases, glutamate dehydrogenase and glutaminase in nitrogen metabolism
Transaminases (aminotransferases) require vitamin B6; transfer amino groups to form α-keto acids and glutamate
Glutamate dehydrogenase converts glutamate to α-ketoglutarate, producing NH4+ (reductive amination or deamination via NAD+/NADH)
Glutaminase converts glutamine → glutamate + NH4+; NH4+ is excreted as urea
Urea biosynthesis (urea cycle): subcellular location and regulation
5 key enzymes: CPS I (mitochondrial), OTC (mitochondrial), argininosuccinate synthetase (cytosol), argininosuccinate lyase (cytosol), arginase (cytosol)
Regulation: CPS I activated by N-acetylglutamate (allosteric activator)
Liver function tests (LFTs): AST and ALT reflect hepatic health; hyperammonemia results from defects in any cycle step
Epigenetics, Genomics & Inheritance
Epigenetics: definitions and scope
Genome: complete set of genetic material in an organism
Genetics: study of individual genes and their inheritance
Epigenome: the full set of epigenetic marks across the genome
Epigenetics: heritable changes in gene expression not caused by DNA sequence changes (e.g., DNA methylation, histone modification, chromatin remodeling, imprinting)
Types of epigenetic modifications
DNA methylation (CpG islands): generally silences gene expression
Histone methylation (HMT) and demethylation (HDM)
Histone acetylation (HAT) opens chromatin and promotes transcription; HDACs remove acetyl groups to repress transcription
Imprinting and developmental reprogramming
Imprinting: selective silencing of one parental allele in certain genes; can affect expression and disease risk if the active allele is mutated
Epigenetic reprogramming during fertilization and implantation erases most marks except imprinted genes
Transgenerational epigenetics: parental experiences can influence offspring via epigenetic mechanisms (e.g., famine exposure, agouti gene methylation, glucocorticoid gene methylation)
Epigenetic diseases and notable studies
Famine studies (Dutch Hunger Winter) showing transgenerational epigenetic effects
Agouti mouse model: methylation status affects phenotype; diet can influence offspring health
Aging and cancer: global hypomethylation and locus-specific hypermethylation with age
Genetic Inheritance, Pedigrees & Population Genetics
Mendelian inheritance overview
Autosomal vs gonosomal (X-linked) inheritance
Dominant vs recessive; penetrance and expressivity; incomplete penetrance and pleiotropy
Heterozygous vs homozygous manifestations; incomplete dominance and codominance possible
Pedigree analysis fundamentals
Pedigree symbols indicate gender, affected status; consanguinity indicated by double lines
Patterns suggesting autosomal recessive vs dominant; X-linked recessive mostly affects males
Mitochondrial inheritance indicated when affected individuals are all maternal descendants
Use Punnett squares to estimate offspring risk (e.g., Aa x Aa → 25% AA, 50% Aa, 25% aa)
X-linked recessive: carrier mother x unaffected male yields 25% affected sons, 25% affected daughters if mother is carrier, etc.
Genetic nomenclature and karyotypes
Chromosome arms: P (short) and Q (long); e.g., 17q indicates long arm of chromosome 17
Common karyotype descriptors: 46, XX; 46, XY; autosomal vs sex chromosome abnormalities
Aneuploidy and mosaicism
Trisomy (2n+1) and monosomy (2n-1); viable trisomies: chromosomes 13, 18, 21; monosomy generally lethal unless gonosomes
Mosaicism: different cell lines with varying chromosomal complements; chromosomal mosaicism vs non-chromosomal mosaicism (gene mutations)
Chromosomal structural abnormalities
Deletion, ring chromosome, microdeletion; inversion, isochromosome; translocations (balanced vs unbalanced; Robertsonian translocations common between acrocentrics 13,14,15,21,22)
Uniparental disomy (two homologous chromosomes from one parent) can disrupt imprinting
FH (Familial Hypercholesterolemia) genetics
Gene mutations: APOB-100 mutation (impaired VLDL transport) and LDLR mutation (impaired uptake)
LDL receptor pathway and feedback regulation by cholesterol
LDL receptor mutations cause autosomal dominant FH; heterozygotes show elevated LDL and premature atherosclerosis; homozygotes more severely affected
LDLR domains and endocytosis: ligand-binding domain, membrane-spanning domain, FxNPxY motif for endocytosis, O-linked sugars
Five classes of FH mutations (I–V) affecting synthesis, folding, ligand-binding, endocytosis, or receptor trafficking
Prevalence: many different mutations across the LDLR gene (allelic heterogeneity)
Clinical Connections: Lipid & Membrane Disorders
Cystic fibrosis (CFTR) and chloride transport
CFTR mutations (e.g., delta-F508) impair chloride and bicarbonate transport; hypertonic sweat and thick mucus; respiratory infections common
CFTR interacts with ENaC in epithelia; defective CFTR disturbs ion and water balance in airways and pancreatic ducts
Ion channels and channelopathies
Brugada syndrome: SCN5A Na+ channel mutation; cardiac arrhythmias and sudden death during sleep; characteristic ECG patterns
Drug interactions with transport and signaling
Omeprazole inhibits H+/K+-ATPase in stomach; cholera toxin increases cAMP via Gs, activating CFTR and causing secretory diarrhea
Stomach acid secretion and intestinal absorption
Gastric parietal cells utilize H+/K+-ATPase for acid secretion; bicarbonate exchange and CO2/H2O conversion; SGLT1 (Na+-glucose cotransporter) for carbohydrate uptake; GLUT2 for basolateral exit
Regulation of blood glucose and lipid handling by hormones
Insulin stimulates fatty acid storage and LPL activity in adipose tissue; glucagon promotes lipolysis
Pharmacology and precision medicine concepts
Pharmacogenomics tailors drug treatment based on individual genomes
CRISPR-Cas9 as a genome-editing tool with Cas9 enzyme and guide RNA; PAM requirements; controversies and emerging therapeutic potential
Lipoprotein Remnants, Transport, and Metabolism (Consolidated)
Dietary fats are emulsified and digested into fatty acids and monoglycerides; absorbed by enterocytes
Chylomicrons assemble in enterocytes (apoB-48-containing); secreted into lymphatics and then blood
In tissues, LPL hydrolyzes TAGs to FFAs for storage or oxidation; chylomicron remnants cleared by liver via apoE interactions
The liver exports VLDL (apoB-100) carrying TAGs; in capillaries, LPL removes TAGs; remnants become IDL and then LDL (cholesterol-rich)
HDL scavenges cholesterol from tissues and returns it to liver; HDL metabolism involves apoA-1 activating LCAT to form cholesterol esters
De novo synthesis of fatty acids proceeds in the cytosol of hepatocytes via citrate shuttle, acetyl-CoA carboxylase forming malonyl-CoA, and fatty acid synthase extending palmitate; the process is regulated by insulin and citrate
Key Formulas and Quick References
De novo fatty acid synthesis (palmitate)
Acetyl-CoA carboxylase reaction (to malonyl-CoA)
Cholesterol biosynthesis (simplified)
Acetyl-CoA + Acetoacetyl-CoA → HMG-CoA
HMG-CoA reductase reduces HMG-CoA to mevalonate (rate-limiting step)
Ketogenesis (ketone bodies)
Acetoacetyl-CoA + acetyl-CoA → HMG-CoA (via HMG-CoA synthase) → acetoacetate via HMG-CoA lyase
Acetoacetate ⇌ 3-hydroxybutyrate (via β-hydroxybutyrate dehydrogenase)
Acetone formed by spontaneous decarboxylation of acetoacetate
Beta-oxidation yields for palmitate (per the material)
129 ATP per palmitate (as stated in notes) in the summarized pathway
Cross-References to Real-World Relevance
Lipid transport balance and disease risk (FH, FH mutations, LDL receptor defects) contribute to premature atherosclerosis and cardiovascular risk; understanding LDLR domain functions helps explain pathogenesis and genotype–phenotype correlations
Epigenetics and transgenerational effects provide insight into how lifestyle and environmental factors can influence disease susceptibility in offspring; agouti model demonstrates a direct link between maternal diet and offspring phenotype
CFTR malfunction and ENaC interaction explain cystic fibrosis pathology and salty sweat; cholera toxin exploits CFTR to cause severe diarrhea, highlighting the importance of ion transport in health and disease
Developmental signaling pathways (Notch, Wnt, SHH, TGF-β/SMAD) tie molecular events to congenital malformations and syndromic disorders (e.g., FGFR-related conditions, HOX gene defects)
Ketogenesis and fatty acid metabolism illustrate metabolic flexibility during fasting or carbohydrate restriction; imbalances can lead to ketosis or ketoacidosis in certain clinical contexts
Glossary of Selected Terms
ApoB-48, ApoB-100: apolipoproteins critical for chylomicron and VLDL/LDL assembly and receptor interactions
LCAT: enzyme that esterifies cholesterol on HDL, promoting maturation
LPL: lipoprotein lipase; hydrolyzes TAGs in circulating lipoproteins in peripheral tissues
HMG-CoA reductase: rate-limiting enzyme in cholesterol biosynthesis; target of statins
CPT I/II: carnitine shuttle enzymes that import fatty acids into mitochondria for β-oxidation
Imprinting: epigenetic marking leading to parent-of-origin–specific gene expression
HOX genes: transcription factors that determine body plan along the anterior–posterior axis
Notch, Wnt, SHH, TGF-β/SMAD: key signaling pathways governing development
FH mutations: autosomal dominant disorder with elevated LDL and risk of early cardiovascular disease
PKU, MSUD, Albinism, Alkaptonuria, Homocystinuria: classic inborn errors of metabolism with specific enzyme defects and dietary interventions
Notes on Specific Data Points from the Transcript
Lipoprotein composition table (summary)
Chylomicrons: apoB-48, apoC-II, apoE
VLDL: apoB-100, apoC-II, apoE
IDL: apoB-100, apoE
LDL: apoB-100
HDL: apoA-1, apoC-II, apoE
LPL activation and TG hydrolysis location: luminal surface of capillary endothelium in adipose tissue and muscle
De novo FA synthesis steps include citrate shuttle, acetyl-CoA carboxylase, NADPH supply from PPP
Alcoholic vs nonalcoholic fatty liver disease causes revolve around VLDL export and apoB-100 handling
Ketone body production is favored in starvation; liver cannot use ketones due to lack of thiophorase; RBCs lack mitochondria
Lipid Synthesis & Storage
Four major plasma lipoproteins (named by density; smallest to highest density) and the four major lipid classes they carry- Chylomicrons (not a true lipoprotein class for density labeling but included): carry dietary TAGs
Very Low Density Lipoproteins (VLDL): carry endogenous TAGs from liver to tissues
Intermediate Density Lipoproteins (IDL/VLDL remnants): remnants after TAG hydrolysis
Low Density Lipoproteins (LDL): deliver cholesterol to cells
High Density Lipoproteins (HDL): pick up cholesterol from tissues and deliver to liver (reverse transport)
Major apolipoproteins by lipoprotein class- Chylomicrons: apoB-48, apoC-II, apoE
VLDL: apoB-100, apoC-II, apoE
IDL: apoB-100, apoE
LDL: apoB-100
HDL: apoA-1, apoC-II, apoE; apoA-1 activates LCAT to produce cholesterol esters
Core structure and function of lipoproteins- Lipoproteins = fat bubbles with a phospholipid exterior and hollow interior that transports TAGs
Cholesterol in the phospholipid membrane helps fluidity while limiting permeability
TAGs stored in hollow interior for transport
Difference between chylomicrons and lipoproteins: TAG origin and apolipoproteins governing circulation
Roles of apolipoproteins and enzymes in lipoprotein metabolism- apoC-II activates Lipoprotein Lipase (LPL) on capillary endothelium; LPL hydrolyzes TAGs in chylomicrons and VLDLs
apoE is used for hepatic uptake of remnants (IDL, chylomicron remnants)
apoB-48: synthesized in intestine for chylomicrons; apoB-100: synthesized in liver for VLDL/LDL
ApoA-1 in HDL activates LCAT (lecithin
--cholesterol acyltransferase) to convert cholesterol to cholesterol esters for HDL
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Lipoprotein transport and the liver- Chylomicron route: dietary fats
lymphatics (lacteals)
bloodstream
tissues (adipose, muscle); remnants taken up by liver via apoB-48 interactions (apoE, apoC-II)
- Chylomicron remnants and LDL receptor
--mediated uptake contribute to hepatic cholesterol management
- Liver roles: packages fatty acids into VLDL for export; performs endocytosis of chylomicrons via apoB-48; central regulator of lipid transport and metabolism
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Lipid storage and utilization in tissues- Adipose tissue stores triacylglycerol (TAG); muscle tissue uses fatty acids for energy
Insulin regulates lipid storage by activating LPL in adipose tissue (and muscle) to hydrolyze TAGs in circulating lipoproteins for storage or energy
Lipoprotein lipase (LPL) activity and TAG hydrolysis- LPL sits on luminal surface of capillaries in adipose and muscle
Activated by apoC-II; hydrolyzes TAGs in circulating lipoproteins to free fatty acids (FFAs) for uptake and storage in adipose tissue or oxidation in muscle
Lipogenesis and TAG storage in the fed state- Insulin promotes fatty acid storage and lipogenesis; citrate exported to cytosol activates acetyl-CoA carboxylase to form malonyl-CoA
Acetyl-CoA carboxylase requires ATP, biotin, and CO2 to form malonyl-CoA
Fatty acid synthase elongates growing fatty acid by 2-carbon units; NADPH (from PPP) provides reducing equivalents
De novo fatty acid synthesis from acetyl-CoA1. Transfer Acetyl-CoA from mitochondria to cytosol via citrate shuttle
Acetyl-CoA cannot cross mitochondrial membranes directly; citrate synthase forms citrate; citrate lyase cleaves citrate to OAA and acetyl-CoA
ext{Acetyl-CoA from citrate}
ightarrow ext{Malonyl-CoA} ext{ via acetyl-CoA carboxylase}
Acetyl-CoA
Malonyl-CoA (AC carboxylase) requires ATP, biotin, CO2
From malonyl-CoA, two-carbon units are added by fatty acid synthase; NADPH supplies reducing equivalents
Palmitate (C16:0) produced as the end product of de novo synthesis
Overall stoichiometry (palmitate synthesis):
Fatty liver diseases and apoB-100 dependence- Alcoholic fatty liver disease: ethanol inhibits VLDL transport from liver; fatty liver results from trapped VLDL and accumulated fatty acids
Nonalcoholic fatty liver disease (NAFLD): related to disruptions in apoB-100 and VLDL export; insulin resistance contributes to impaired lipoprotein processing
Triacylglycerol synthesis in liver and adipose tissue- TAGs are synthesized in liver by combining 3 fatty acids with glycerol-3-phosphate head
Glycerol-3-phosphate sources:
Phosphorylation of free glycerol via glycerol kinase
Reduction of DHAP via glycerol-3-phosphate dehydrogenase (adipose and liver)
Adipose tissue lacks glycerol kinase and relies on glucose uptake to generate DHAP for TAG synthesis
Cholesterol biosynthesis and regulation- Pathway overview 1) Acetyl-CoA + Acetoacetyl-CoA
HMG-CoA 2) HMG-CoA reduced by HMG-CoA reductase to mevalonate (rate-limiting step)- Denoted as the rate-limiting enzyme; inhibited by cholesterol, glucagon, and statins
3) Mevalonatecholesterol through several steps
<!-- -->Key regulatory enzyme
HMG-CoA reductase (rate-limiting in cholesterol de novo synthesis)
Regulation and clinical relevance
Negative feedback by cholesterol; pharmacologic statins inhibit HMG-CoA reductase to lower cholesterol synthesis
Cytoskeleton & Extracellular Matrix (ECM)
Three major types of cytoskeletal filaments- Actin Filaments (microfilaments)
Polarity with barbed (+) and pointed (-) ends; subunits: G-actin (globular) and F-actin (filamentous)
Polymerization helpers:- Formin: nucleates and elongates, adds ATP-bound G-actin to barbed end
Profilin: promotes ATP binding on G-actin
Arp2/3: nucleates new branches and growth
Capping proteins: cap both ends to prevent depolymerization
Coflin: cleaves filament to create new ends for growth
Roles: contractile rings in cytokinesis; vesicular transport highways; microvilli structure (fimbrin, villin as bundling proteins)
Structures: pseudopodia, lamellipodia, filopodia
Microtubules
Composed of \alpha- and \beta-tubulin dimers; form hollow tubes with minus end anchored at centrosome (\gamma-tubulin ring) and plus end outward
Microtubule-associated proteins (MAPs): polymerases and depolymerases
Motor proteins: kinesin (anterograde, toward plus end), dynein (retrograde, toward minus end)
Cilia & flagella: 9+2 microtubule structure; dynein drives bending motions
Intermediate Filaments
Dimer-based, tetramer assembly; form apolar filaments (twizzler-like)
Provide mechanical resilience and connect to desmosomes/hemidesmosomes
ECM components and their roles- Fibrous proteins: collagen (most abundant; triple helix with glycine every third residue; hydroxyproline contributes to scurvy), forms bone, tendon, basal lamina; basal lamina filters molecules
Glycosaminoglycans (GAGs) & Proteoglycans: repeating disaccharide units; proteoglycans bind core proteins; hyaluronan is a unique, non-sulfated GAG; proteoglycans form aggregates (aggrecan) and form a gel-like ECM
Adhesion proteins: fibronectin (binds proteoglycans to collagen; recognized by integrins), laminin (forms networks in basal laminae)
Diseases linked to ECM/cytoskeleton disruptions- Scurvy: vitamin C deficiency; impaired prolyl hydroxylase
weakened collagen; symptoms include gingival bleeding, skin lesions
Osteogenesis Imperfecta: COL1A1/COL1A2 mutations (type I collagen)
brittle bones
Ehlers-Danlos Syndrome: COL3A1 mutation (type III collagen)
hyperflexible skin, joints, tissue fragility
Marfan Syndrome: FBN1 mutation (fibrillin-1)
abnormal TGF-\beta signaling; arachnodactyly, lens dislocation, risk of aortic aneurysm/dissection
Loeys-Dietz Syndrome: mutations in TGFBR1/2 or SMAD3
severe cardiovascular manifestations without lens subluxation
Deafness: GJB2 (connexin-26) mutations affecting gap junctions in the ear
Cell
-ECM junctions and adhesion structures- Focal adhesions: actin
-
integrin connections via talin, vinculin, and \alpha-actinin
- Hemidesmosomes: intermediate filament
integrin connections to the basal lamina
- Desmosomes: cadherin-based cell
-cell junctions linked to intermediate filaments
- Tight junctions (occludin, claudins): seal epithelial layers
- Gap junctions: connexins forming channels for intercellular communication
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Cell Membranes & Cellular Homeostasis
Membrane composition and properties- Phospholipids: amphipathic; hydrophilic head (choline, phosphate, glycerol) and hydrophobic tails (often cis double bonds for fluidity)
Phosphoglycerides, sphingolipids, and glycolipids (glycolipids face extracellular surface) comprise the membrane
Lipid rafts: microdomains rich in cholesterol, sphingolipids, and certain proteins; promote coordinated signaling
Gangliosides: glycolipids with sialic acids; Tay-Sachs disease due to HEXA frameshift mutation leading to accumulation of gangliosides in lysosomes
Cholesterol: modulates membrane rigidity and permeability
Membrane-associated proteins- Flippase: flips phospholipids across leaflets (rare, but contributes to asymmetry)
Lectins: proteins that bind carbohydrate sequences on cells (e.g., leukocytes, platelets, epithelial cells)
Membrane transport mechanisms- Carriers: undergo conformational changes; may be active or passive
Channels: can be constitutively open or ligand-gated; selective for ions/molecules
Endocytosis / Exocytosis
Phagocytosis, Caveolae-mediated endocytosis, Receptor-mediated endocytosis, Transcytosis
Aquaporins and ion channels: selective for substrates based on size and pore properties
Key transporter systems and clinical examples- CFTR: chloride channel; mutations cause cystic fibrosis (autosomal recessive) with hypertonic sweat and respiratory infections; CFTR modulates ENaC activity in epithelia
Cholera toxin: activates adenylyl cyclase via Gs, raises cAMP, opens CFTR
Cl- and water secretion into intestinal lumen (secretory diarrhea)
- Na+/K+ ATPase: basolateral pump maintaining gradients (example in gastric parietal cells for acid secretion)
- Omeprazole: inhibits H+/K+
ATPase (gastric acid secretion)
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Receptors and signaling architectures- Receptors: extracellular ligand binding triggers intracellular signaling
Intracellular signaling often begins with receptor activation and propagates via second messengers or kinase cascades
Receptors & Cell Signaling
General signaling framework
1) Signaling cell emits ligand; receiver cell must have compatible receptor
2) Receptor activation triggers intracellular signaling cascades
3) Signaling cascades alter effector proteins and cell behavior
Categories of extracellular signaling and receptor types- Intracellular signals: hydrophobic molecules (steroids, NO) can diffuse through membranes and bind intracellular receptors (nuclear receptors) to modulate transcription
Extracellular signals: hydrophilic or large molecules (peptides, growth factors, prostaglandins, neurotransmitters) often bind surface receptors
Peptide hormones vs neuropeptides vs growth factors
Neurotransmitters act at ligand-gated ion channels or GPCRs
Eicosanoids (e.g., prostaglandins) bind cell-surface receptors
Key receptor families and pathways- Ion-channel coupled receptors (ionotropic): ligand-gated ion channels regulate ionic flow and neuronal signaling
G protein-coupled receptors (GPCRs): 7-transmembrane domain receptors; signal via G proteins (Gs, Gi, Gq)
Gs: activates adenylyl cyclase
↑cAMP
Gi: inhibits adenylyl cyclase
↓cAMP
Gq: activates phospholipase C
IP3 and DAG; IP3 raises intracellular Ca2+, DAG activates protein kinase C (PKC)
- Receptor tyrosine kinases (RTKs): ligand-induced dimerization and trans-phosphorylation; downstream pathways include Ras
Raf
MEK
ERK; drives cell growth and differentiation
- Tyrosine kinase
-
associated receptors: JAK/STAT signaling
- Receptor guanylyl cyclases: produce cGMP as second messenger
- Serine/threonine kinase receptors: TGF-\beta signaling via SMAD transcription factors
- Notch signaling: proteolytic cleavage releases intracellular domain that acts as transcription factor in nucleus
- Wnt/Frizzled signaling: \beta-catenin stabilization and transcriptional activation
- Hedgehog/Patched-Smoothened: Hedgehog ligand relieves Patched inhibition; Smoothened promotes transcription
- SHH, FGFs, BMPs, Nodal and related players in development
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Notable downstream pathways and second messengers- cAMP: formed by adenylyl cyclase; degraded by phosphodiesterases; activates PKA
cGMP: formed by guanylyl cyclase; degrades by phosphodiesterases; activates PKG, ion channels
IP3/DAG: PLC cleaves PIP2 to generate IP3 (Ca2+ mobilization) and DAG (PKC activation)
MAPK cascade: Ras
Raf
MEK
ERK; drives cell growth and differentiation
JAK/STAT: cytokine receptors activate JAK; STATs translocate to nucleus to drive transcription
TGF-\beta/SMAD: serine/threonine kinase receptors phosphorylate SMADs; SMADs regulate transcription
NF-\kappaB: resting I\kappaB inhibits NF-\kappaB; stimuli activate I\kappaB kinase
degrad
ation of I\kappaB
NF-\kappaB translocates to nucleus
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Integrins and signaling- Integrins link ECM to cytoskeleton in focal adhesions and can initiate signaling via focal adhesion kinase (FAK) autophosphorylation
Death receptors and apoptosis- Fas receptor family (death receptors) cluster cytosolic death domains to trigger intrinsic apoptosis or inflammatory signaling
Lipid Mobilization, Catabolism & Ketone Bodies
Fatty acid mobilization and transport- Lipolysis in adipose tissue liberates FFAs and glycerol from TAGs via hormone sensitive lipase (HSL) activation by glucagon/epinephrine
FFAs bind albumin in blood for transport to tissues
Mitochondrial entry of fatty acids for beta-oxidation- Activation: fatty acids are converted to fatty acyl-CoA by acyl-CoA synthetase (acyl-CoA formation requires ATP)
Outer mitochondrial membrane: carnitine palmitoyltransferase I (CPT I) transfers the fatty acyl group to carnitine
Inner mitochondrial membrane: CPT II transfers the fatty acyl group back to CoA inside matrix
Beta-oxidation in mitochondria yields acetyl-CoA, FADH2, and NADH; acetyl-CoA enters TCA or ketogenesis depending on metabolic state
Beta-oxidation yield (palmitate, C16:0)- Beta-oxidation cycles yield 7 FADH2, 7 NADH, and 8 acetyl-CoA per palmitate
Per palmitate, total ATP yield is given as:
In this material, the total yield is stated as 129 ATP per palmitate
Carnitine role and disorders- Carnitine shuttles long-chain fatty acids into mitochondria
Deficiencies: CPT II deficiency (myopathic symptoms, brown urine), carnitine deficiency (muscle pain, high triglycerides)
Peroxisomal defects (Zellweger syndrome) affect VLCFA metabolism; phytanic acid accumulation with Phyh deficiency
Peroxisomal transport and VLCFA metabolism- VLCFAs require peroxisomes for \beta-oxidation; defects disrupt metabolism
Ketone bodies and ketogenesis- Ketone bodies: acetone, 3-hydroxybutyrate, acetoacetate
Ketogenesis in liver mitochondria: HMG-CoA synthase and HMG-CoA lyase generate ketone bodies
Rate-limiting step: HMG-CoA synthase (in ketogenesis)
Ketone bodies serve as fuels for extrahepatic tissues during fasting or carbohydrate deprivation; brain and muscle can utilize ketones; liver and RBCs cannot use ketone bodies (liver lacks thiophorase; RBCs lack mitochondria)
Ketosis and ketoacidosis can occur in alcohol abuse, Type I diabetes, prolonged fasting, and some children; acetone imparts fruity breath
Fatty Liver Disease, Metabolism & Regulation
Alcoholic fatty liver disease- Ethanol inhibits VLDL export from liver; cholesterol synthesis and palmitate production continue, but VLDL cannot leave the liver
Nonalcoholic fatty liver disease (NAFLD)- Often linked to apoB-100 transport defects and hepatic lipid accumulation; insulin resistance contributes to NAFLD progression
Regulation of hepatic VLDL secretion by diet & hormones- Fed state: insulin promotes lipogenesis; insulin also activates LPL to process circulating lipoproteins
LPL action on VLDL and chylomicrons hydrolyzes TAGs to FFAs for storage or energy
Cholesterol Biosynthesis & Regulation (Expanded)
Pathway overview- Acetyl-CoA + Acetoacetyl-CoA
HMG-CoA
HMG-CoA reductase reduces HMG-CoA to mevalonate (rate-limiting step)
Mevalonate
-
cholesterol through downstream steps
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Regulation of HMG-CoA reductase- Inhibited by cholesterol via negative feedback, by glucagon, and by statins
Activation stimulates cholesterol synthesis; regulation matches cellular cholesterol needs
Hormones, Signaling & Genomic Regulation
Hormone types and hydrophilicity/hydrophobicity- Hydrophilic hormones (e.g., peptide hormones, catecholamines): stored in vesicles; short-to-intermediate half-lives; act on surface receptors
Hydrophobic hormones (steroids, thyroid hormones): diffuse through membranes; long half-lives; often bind to intracellular receptors (nuclear receptor family), regulating gene transcription
Four signal transduction pathways for hydrophilic hormones- Integrin-mediated signaling (growth signals)
Ligand-gated ion channels (neurohormones)
Receptor tyrosine kinases / receptor enzymes (example: leptin via JAK/STAT)
GPCRs (adenylyl cyclase
--cAMP, PKC