Estructura, transporte y requerimiento biológico del colesterol

Un análisis mecanístico de la partición en compartimentos, lipoproteína requisitos estructurales y el mínimo estimado por el modelo para el sistema de transporte circulatorio

Resumen

Antecedentes. De cuerpo entero colesterol la distribución, los requerimientos estructurales de las lipoproteínas y la dependencia tisular del colesterol circulante se confunden con frecuencia en fuentes clínicas y educativas, lo que lleva a exageraciones sobre cuánto colesterol circulante “requiere” el cuerpo.”

Métodos. Este análisis (i) define un vocabulario estricto basado en compartimentos que distingue entre el colesterol corporal total, el colesterol tisular, el colesterol intracelular y el colesterol circulante (plasmático/sérico), y (ii) construye una estimación transparente mediante un modelo de transporte para la concentración mínima de colesterol circulante requerida para mantener la integridad estructural de las lipoproteínas y satisfacer la demanda tisular exógena, con supuestos declarados, parámetros con conversión de unidades explícita y límites de sensibilidad. Las ecuaciones y los rangos de parámetros se indican en el apéndice de Métodos (Sección 11).

Hallazgos. (1) El colesterol corporal total en un adulto es de aproximadamente 120–150 g; el conjunto plasmático de intercambio rápido es de 3–7 g (dependiendo del volumen plasmático y medido colesterol total (concentración) representa entre 2 y 51 TP9T del contenido corporal. (2) Solo el cerebro contiene aproximadamente entre 30 y 35 g, aislados del plasma mediante el barrera hematoencefálica. (3) El colesterol plasmático es de ~70% esterificado / ~30% libre. (4) Un modelo representativo de 22 nm LDL Una partícula (reconstrucción de Hevonoja) contiene aproximadamente 2,200 moléculas de colesterol, de las cuales aproximadamente 18% son colesterol libre de superficie; el LDL es heterogéneo y estas cifras no deben aplicarse sin crítica a todas las partículas de LDL. (5) Bajo los supuestos del modelo de transporte mencionado y utilizando recuentos de partículas consistentes con la RMN (LDL-P en nmol/L → ~10¹⁶–10¹⁷ partículas/dL; HDL-P en µmol/L → ~10¹⁸ partículas/dL), el colesterol total plasmático mínimo estimado por el modelo que estabiliza simultáneamente el sistema de lipoproteínas y satisface ~50 mg/día de demanda exógena neta en un adulto no embarazada es de aproximadamente 50–90 mg/dL (sensibilidad 40–110 mg/dL). Se trata de un escenario calculado, no de un mínimo fisiológico demostrado.

Conclusiones. El promedio de colesterol total plasmático en adultos estadounidenses modernos de ~188 mg/dL (NHANES 2017–2018) supera el límite mínimo de transporte estimado por el modelo en un factor que depende de los supuestos, pero que es consistentemente > 2. El excedente es tolerado metabólicamente, está vinculado causalmente al riesgo de ASCVD sobre la base de cada partícula de apoB y no es necesario para ninguna función fisiológica conocida. Las guías clínicas que recomiendan la reducción de LDL-C para la prevención de ASCVD operan en un registro epistémico diferente (reducción de eventos en ensayos clínicos) que este artículo (modelación de balance de masa); los dos son complementarios, no están en conflicto.

1. Vocabulario basado en compartimentos

Cada afirmación sobre el colesterol en este artículo especifica (i) el compartimento, (ii) la forma química y (iii) las unidades. Confundir las concentraciones del panel lipídico clínico con la masa de colesterol en los tejidos o en todo el cuerpo es la fuente de la mayoría de los errores cuantitativos en la literatura divulgativa y educativa. A lo largo del texto se utiliza la siguiente terminología. [1]

Término	Significado	Unidades típicas
Colesterol total en plasma / colesterol total en suero	Concentración de colesterol total en la fracción sanguínea correspondiente (calculada o medida directamente en un perfil lipídico de rutina)	mg/dL o mmol/L
LDL-C / HDL-C / VLDL-C en plasma	Colesterol transportado por la clase de lipoproteína mencionada en el plasma	mg/dL o mmol/L
LDL-P / HDL-P	Concentración numérica de LDL o HDL partículas (típicamente medidas por espectroscopía de RMN)	LDL-P en nmol/L; HDL-P en µmol/L (tener en cuenta los diferentes órdenes de magnitud)
Colesterol libre plasmático / plasma éster de colesterilo	Distribución química del colesterol plasmático entre las formas no esterificadas y esterificadas (por lo general, ~30% / ~70%)	mg/dL, mmol/L o % de colesterol total (CT) en plasma
Masa de colesterol plasmático	Plasma CT × volumen plasmático; la masa absoluta de colesterol circulando en el plasma en un momento dado	g (= mg/dL × dL_plasma / 1000)
Masa de colesterol circulante	Masa de colesterol plasmático + colesterol transportado en membranas eritrocitarias (se intercambia rápidamente con el plasma)	g
Concentración de colesterol en los tejidos	Colesterol por unidad de masa de tejido (p. ej., cerebro a ~23 mg/g de peso húmedo)	mg/g de peso húmedo o seco
Colesterol celular / subcelular	Colesterol en un tipo celular específico, en la membrana de un orgánulo o en un fondo común	mol% de lípidos de membrana; µg/mg proteína
Colesterol corporal total	Masa total de colesterol corporal en todos los tejidos y líquidos	g
Piso de transporte estimado por el modelo	Concentración plasmática mínima de colesterol calculada que satisface las funciones estructurales y de entrega del sistema de lipoproteínas circulantes bajo los supuestos establecidos	mg/dL

 

■ Las unidades de partículas de lipoproteínas son convenciones de RMN El análisis de subfracciones de lipoproteínas por RMN (LipoProfile y similares) informa la LDL-P en nanomoles por litro (nmol/L), lo que refleja el rango típico de ~10¹⁵–10¹⁸ partículas/L en adultos. La HDL-P se informa convencionalmente en micromoles por litro (µmol/L) debido a que las HDL son más abundantes por partícula. Este artículo utiliza las convenciones de la RMN en todo momento y realiza la conversión a partículas por dL mediante aritmética explícita.

 

■ Plasma vs. suero Los perfiles lipídicos clínicos de rutina se realizan tanto en suero como en plasma; la diferencia en los valores de colesterol medidos es mínima (por lo general, < 3%). A menos que se especifique lo contrario, todas las concentraciones de colesterol circulante se refieren indistintamente al plasma o al suero.

2. Distribución sistémica y balance de masa

2.1 Colesterol corporal total

El colesterol corporal total en un adulto es de aproximadamente 120–150 g, con escala de peso corporal. El rango refleja la variabilidad entre sujetos y entre métodos en los estudios de distribución en tejidos. [2][3Las citas de libros de texto antiguos de ~35 g representan solo el grupo A de intercambio rápido de Goodman (hígado + plasma + eritrocitos + parte de las vísceras) en el modelo de trazadores cinéticos, no el contenido de todo el cuerpo. El análisis tisular cuantitativo directo (Sabine, 1977, recapitulado en revisiones modernas) sitúa el colesterol corporal total humano adulto en la cifra más alta, con el cerebro, el tejido conjuntivo, incluido el adiposo, y el músculo esquelético contribuyendo cada uno con aproximadamente 25–35 g.2][3]

El modelo de trazador de tres compartimentos de Goodman define un compartimento A de intercambio rápido (hígado, plasma, eritrocitos, esplácnico) de 15 a 30 g, un compartimento B de intercambio lento (músculo esquelético, tejido adiposo, tejido conectivo denso) de 35 a 60 g, y un compartimento del SNC cinéticamente aislado de ~30 a 35 g.4][5El compartimento plasmático por sí solo contiene 3–7 g de colesterol, dependiendo del volumen plasmático y de la concentración plasmática total de colesterol medida.

2.2 Distribución en tejidos

Distribución bajo el supuesto de ~140 g de colesterol corporal total (punto medio representativo). Todas las entradas son la masa de colesterol en los tejidos. [2][3]

Compartimiento	Colesterol (g)	% del total del cuerpo	Forma química dominante
Cerebro / SNC (mielina + membranas neuronales)	30–35	~22–25%	>99,51 TP9T libre (no esterificado)
Músculo esquelético	~25–30	~18–22%	Libre (membrana plasmática)
Tejido conectivo, tejido adiposo, líquidos corporales	~25–32	~18–23%	Mixto; la CE se acumula con la edad en el tendón/duramadre
Piel	~12–18	~9–13%	Gratis
Otras vísceras (pulmón, riñón, intestino, etc.)	~12–18	~9–13%	Gratis de forma predominante
Hígado	~4–6	~3–4%	FC + CE mixto
Plasma / reserva circulante	3–7	~2–5%	~70% CE / ~30% FC
Corazón, bazo, suprarrenales (por órgano)	<1 cada uno	<1%	High density per gram (adrenals ≥ 25 mg/g)

The CNS contains ~22–25% of body cholesterol at the highest tissue concentration (~23 mg/g wet weight). [5][6] The blood–brain barrier is impermeable to lipoprotein cholesterol; the entire CNS pool is synthesized locally. Cortical neuronal cholesterol turns over with a half-life of 6 months to 5 years; myelin cholesterol turns over on the order of decades. Net efflux from the CNS occurs primarily as 24S-hidroxicolesterol, which traverses the blood–brain barrier and is cleared in plasma. [5][6][7]

2.3 Plasma cholesterol mass at different plasma total cholesterol concentrations

Plasma cholesterol mass is the product of plasma volume and plasma total cholesterol concentration. At a representative plasma volume of 3.0 L:

Plasma TC (mg/dL)	Plasma cholesterol mass (g, 3.0 L plasma)	Clinical context
50	1.5	Below typical neonatal range; rare LOF mutations
80	2.4	Reported PCSK9 LOF homozygote range
100	3.0	inhibidor de PCSK9 on-treatment targets
150	4.5	Therapeutic target on intensive lipid-lowering
188	5.6	US adult mean (NHANES 2017–2018) [8]
220	6.6	Borderline-elevated
280	8.4	Heterozygous FH range

 

■ Plasma volume varies with body size Plasma volume in adults is approximately 40–45 mL/kg body weight (~2.8–3.2 L for a 70-kg adult, ~3.5–4.0 L for a 90-kg adult). All plasma mass calculations in this paper use a representative 3.0 L unless otherwise stated.

2.4 Subcellular distribution and the ER cholesterol sensor

Within most non-neural cells, the plasma membrane holds 60–90% of cellular cholesterol at 30–40 mol% of PM lipids, while the endoplasmic reticulum maintains only 3–6 mol%. [9][10] The gradient is enforced by SREBP2 coupled to SCAP and Insig: when ER cholesterol exceeds ~5 mol%, SCAP retains SREBP2 in the ER and synthesis is suppressed. [11] Das et al. (eLife 2014) resolved PM cholesterol into three functional pools using a Perfringolysin O (PFO*) probe: a sphingomyelin-sequestered pool (~15 mol% of PM lipids), an “essential” pool required for cell viability, and an “accessible” pool that fluxes to the ER to regulate synthesis. [11][12] The accessible pool—not bulk PM cholesterol—is the regulatory signal.

▲ PFO* binding threshold applies to plasma-membrane bilayers, not lipoprotein monolayers. The 35 mol% PFO*-accessibility threshold in plasma membranes reflects bilayer architecture and sphingomyelin–cholesterol complexation specific to the PM. [11][12] LDL and HDL surfaces are phospholipid monolayers stabilized by apolipoproteínas; they have different lipid composition, leaflet asymmetry, and packing constraints. The threshold should not be applied directly to lipoprotein surfaces without further analysis.

2.5 Daily turnover

Whole-body de novo síntesis de colesterol in adults is approximately 10 mg/kg/day (~700 mg/day in a 70-kg adult, ~880 mg/day in an 88-kg adult). The liver contributes only ~10% of total synthesis in humans; the majority is extrahepatic. [13] Three-pool tracer studies of plasma cholesterol turnover give a total production rate (synthesis plus dietary absorption) of ~1.0–1.2 g/day in normolipidemic subjects. [4] Dietary intake (~300–500 mg/day on a Western diet, ~30–50% absorbed) is compensated by down-regulation of endogenous synthesis. [14]

3. Lipoprotein Architecture and Cholesterol Partitioning

3.1 Representative 22-nm LDL particle composition

The reconstruction below is from Hevonoja et al. (BBA 2000) for a representative LDL particle of 22 nm diameter. [15][16][17]

Component	Molecules / particle	Mass fraction (%)	Ubicación
Cholesteryl esters (CE)	~1,600	40–45%	Core
Unesterified cholesterol (FC)	~600	8–10%	~400 surface, ~200 core
Triglicéridos (TG)	~170	5–9%	Core
Phosphatidylcholine	~450	} 19–21% combined	Surface monolayer
Sphingomyelin	~185	(phospholipid total)	Surface monolayer
ApoB-100 (single copy)	1	20–25%	Wraps the surface

Total cholesterol per representative LDL particle is ~2,200 molecules; surface FC accounts for ~18% of colesterol LDL. Some general references cite ~1,500 cholesterol per average LDL particle, reflecting different averaging schemes across the LDL size distribution; both numbers are central-tendency descriptions of an inherently heterogeneous population. [16]

▲ LDL is heterogeneous. In-vivo LDL spans ~22–27.5 nm with substantial compositional variation; LDL pequeño y denso carries less cholesterol per particle and is enriched in TG, while large buoyant LDL carries more. The Hevonoja reconstruction is a representative central-tendency particle and should not be applied uncritically to all LDL species.

3.2 Plasma free-to-esterified ratio

Direct enzymatic and chromatographic measurement in healthy human serum shows plasma free cholesterol at ~25–30% of total plasma cholesterol, with the esterified fraction at ~70–75%. [18][19] An elevated FC/CE ratio is associated with LCAT dysfunction, familial chylomicronemia, and an independent atherogenic signal in some studies. [20]

3.3 Surface free cholesterol: structural role

Free cholesterol on the lipoprotein surface intercalates between phospholipid acyl chains, with its 3β-hydroxyl projecting into the aqueous interface and its rigid esterol ring aligned with the lipid tails. This “condensation” reduces free volume in the monolayer, decreases its permeability to water, and increases mechanical stability of the particle. [21][22] FC at ~25 mol% of surface lipids is compatible with a liquid-ordered, well-packed monolayer; this configuration supports particle stability and lateral mobility for enzymatic processing. [23]

3.4 Free cholesterol exchange

Free cholesterol on lipoprotein surfaces is in spontaneous equilibrium with cell membranes and other lipoprotein particles via passive aqueous diffusion. Exchange half-time scales inversely with surface curvature: ~5 min for nascent HDL, ~45 min for LDL. [21][23] This kinetic system maintains a near-uniform thermodynamic activity of cholesterol across all extracellular lipid surfaces. [22][23]

4. Cholesteryl Esters: Transport Cargo

Cholesteryl esters are fully hydrophobic and reside in the lipoprotein core as a liquid or liquid-crystalline droplet. CE in LDL represents 40–45% of particle mass and provides the bulk of cholesterol delivered to cells via receptor-mediated endocytosis, where lysosomal acid lipase liberates free cholesterol for use. [17]

CETP shuttles CE from HDL to apoB-containing lipoproteins in exchange for triglycerides, enriching apoB particles with cholesterol cargo. A substantial fraction of apoB-particle core CE therefore reflects cholesterol that has cycled through peripheral cells, plasma, and HDL before being transferred onto LDL, superimposed on hepatic cholesterol pools secreted as VLDL. [24]

5. HDL Maturation

Nascent HDL is secreted as lipid-poor apoA-I that acquires phospholipid and free cholesterol from peripheral cells via ABCA1, forming a discoidal particle of two apoA-I molecules in a “double-belt” conformation. [25] LCAT, activated by apoA-I, transfers an acyl group from the sn-2 position of phosphatidylcholine to surface FC, generating CE that migrates into the hydrophobic core. [23][25]

As CE accumulates, the discoidal bilayer becomes spherical. Mature HDL2 reaches ~10–12 nm diameter and carries ~30–60 cholesterol molecules per particle (mostly CE), with ~5–15 surface FC. [23] The CE either returns directly to the liver via SR-B1 or transfers to apoB particles via CETP for hepatic clearance through LDLR. [23][24]

6. Tissue Requirements: De Novo Synthesis and Exogenous Uptake

6.1 Most nucleated tissues can synthesize cholesterol de novo

Every nucleated cell in the human body expresses the complete mevalonate–cholesterol biosynthetic pathway. [13][26] Under usual conditions, most tissues are not absolutely dependent on continuous exogenous cholesterol supply from plasma; the quantitative balance between local synthesis and lipoprotein-derived uptake varies by tissue, age, and physiological state.

Tissue	Primary cholesterol source	Notes
Brain / CNS	Local synthesis (astrocitos → neurons via apoE)	BBB excludes lipoprotein cholesterol; net efflux via 24S-OH-cholesterol [7]
Músculo esquelético	Predominantly local synthesis	Low demand for new sterol
Piel	~90% local synthesis	Supports barrier function
Adrenal cortex	Mixed: LDLR > SR-B1 in humans; reverse in rodents [27][28]	Stored CE buffers acute steroidogenic demand
Gonads (testes, ovaries)	Mixed: LDLR + SR-B1; reproductive-state-dependent	Pregnancy and lactation raise demand
Placenta	Maternal LDL and HDL; pregnancy only	Outside scope of nonpregnant adult analysis
Hígado	Synthesis + dietary + reverse transport	Master regulator; secretes VLDL

In human adrenocortical and gonadal physiology, LDLR-mediated endocytosis carries greater quantitative weight than SR-B1 for cholesterol delivery — opposite to the rodent pattern in which SR-B1 dominates. SR-B1 nonetheless remains expressed and biologically active in human steroidogenic tissues, and SR-B1 loss-of-function in humans produces subtle but real abnormalities in ACTH-stimulated cortisol response. The mixed-pathway nature of human steroidogenic cholesterol supply should be preserved in any mechanistic discussion. [27][28]

6.2 LDL-receptor kinetics: in-vitro and in-vivo are not interchangeable

In-vitro: in cultured human fibroblasts, high-affinity binding of LDL apoB-100 saturates at LDL protein concentrations below 50 µg/mL (Brown & Goldstein). [29][30] Catapano and colleagues (2024) describe this as a half-saturation corresponding to an LDL-C plasma equivalent of ~2.5 mg/dL, and combine it with the observation that interstitial-fluid LDL-C is ~20% of plasma LDL-C to argue that plasma LDL-C of ~12.5 mg/dL would saturate tissue LDLR. [31] This argument depends on intermediate assumptions about LDL protein-to-cholesterol mass ratio, interstitial-fluid composition, and uniformity of fibroblast LDLR behavior; this paper cites the argument without endorsing it as a measured human threshold.

In-vivo: organ-level LDL clearance in rat and hamster (Spady & Dietschy) gives Km ≈ 90 mg/dL — roughly 30-fold higher, reflecting unstirred boundary layers, capillary permeability, and receptor density rather than intrinsic affinity. [32] This rodent in-vivo number is not directly portable to human tissue-level cholesterol-delivery thresholds.

▲ Receptor saturation kinetics are not a clean human delivery threshold. The chain (in-vitro fibroblast Km → plasma-equivalent LDL-C → interstitial-fluid LDLR saturation in adrenal/gonadal cells) depends on assumptions that have not been independently validated in humans, and hepatocytes are exposed to sinusoidal blood rather than to ordinary interstitial fluid. The substantively defensible claim is empirical: humans with very low plasma LDL-C, by genética or therapy, have not shown clinical signs of cholesterol-delivery insufficiency in the reported populations.

6.3 Empirical observations: very low LDL-C in humans

Carriers of homozygous PCSK9 loss-of-function mutations are a small reported sample. The originally described Dallas Heart Study African-American homozygotes had lifelong plasma LDL-C of 14–29 mg/dL (total cholesterol typically 50–80 mg/dL) without overt clinical abnormalities in the limited published descriptions. [33][34] The total reported global population of such homozygotes remains small, so this evidence supports the absence of large-effect harm but does not prove a universal physiological minimum.

Larger evidence comes from PCSK9-inhibitor randomized trials. Fourier (n = 27,564) had a median randomized follow-up of 2.2 years, with on-treatment median LDL-C of 30 mg/dL and no signal of adrenal insufficiency, hypogonadism, cognitive decline, derrame cerebral hemorrágico, or muscle disease. [35] Odisea OUTCOMES (n = 18,924) had a median follow-up of 2.8 years with similar safety findings. [36] The FOURIER Open-Label Extension (FOURIER-OLE, n = 6,635 of the original 27,564) added a median 5.0 years de evolocumab exposure, bringing exposición acumulativa in that subset to ~8.4 years, with no new safety signal. [37] These are large, prospective safety data; they are not a direct measurement of human cholesterol delivery thresholds but they bound the empirically demonstrated safe range of plasma LDL-C from above.

Interstitial-fluid LDL is reported at ~10–20% of plasma LDL concentration in human peripheral lymph studies. [38][39] These data are descriptive and do not establish a measured human tissue saturation threshold.

7. A Transport-Model Estimate of the Minimum Circulating Cholesterol

■ What this section is and is not. This section presents a transport-model estimate of the minimum plasma cholesterol concentration that simultaneously (i) sustains the structural integrity of the circulating lipoprotein system and (ii) supplies the net daily exogenous cholesterol demand of a nonpregnant adult under usual conditions. The estimate is calculation, not measurement. Equations and parameter values are in Section 11.

7.1 Structural integrity

All circulating lipoprotein particles require surface free cholesterol to stabilize their phospholipid monolayer. Using NMR-consistent particle counts (LDL-P in nmol/L; HDL-P in µmol/L) and explicit unit conversion: [15][17]

Particle class	Class concentration (clinical)	Particles per dL	Surface FC per particle	Surface FC contribution (mg/dL)
LDL	LDL-C 100 mg/dL; LDL-P ~1,200 nmol/L	~7.1 × 10¹⁶	~400	~18
HDL	HDL-C 50 mg/dL; HDL-P ~30 µmol/L	~1.8 × 10¹⁸	~10	~12
VLDL / IDL	TG-driven; particle counts ~10¹⁵–10¹⁶ /dL	—	~variable	~2–3
Total surface FC (model, baseline TC ~190)	—	—	—	~30–33
Total measured plasma FC (~28% of TC at TC 190)	—	—	—	~50–55 (includes core FC and other)

The model-derived surface FC of ~30–33 mg/dL at typical clinical lipid values, plus core FC of ~10–15 mg/dL (LDL has ~200 core FC per particle, HDL has a smaller core FC contribution), and a small chylomicron-remnant and Lp(a) contribution, sums to approximately 45–55 mg/dL plasma FC. This matches the directly measured plasma FC fraction of ~25–30% of total cholesterol at total cholesterol ~190 mg/dL. [18][19]

7.2 Net daily exogenous cholesterol delivery to peripheral tissues

Reverse cholesterol transport tracer studies in healthy adults (Turner et al., 2012) estimate whole-body tissue FC efflux at 3.79 ± 0.88 mg/kg/h, reported in the original paper as ≈8 g/day; this corresponds to ~6.4 g/day at 70 kg or ~8 g/day at 88 kg (the study’s mean approximate body weight). [40] This is bidirectional exchange flux, not net delivery demand. Estimated net obligate exogenous uptake by tissues whose local synthesis is insufficient under baseline conditions, in a nonpregnant adult, is approximately:

Tissue / function	Estimated daily cholesterol use	Source of supply
Adrenal steroidogenesis (baseline)	~30–60 mg/day	Mostly LDLR-mediated; SR-B1 contribution
Gonadal steroidogenesis (nonpregnant adult, baseline)	< 10 mg/day	Predominantly LDLR-mediated in humans
Bile acid synthesis	~400 mg/day	Hepatic pool; not a peripheral demand
Extrahepatic membrane turnover (all)	~600–700 mg/day	Met by local synthesis
Net obligate exogenous demand (nonpregnant adult, baseline)	Order of tens of mg/day (~50 mg/day central estimate)	Met at very low plasma LDL-C

 

▲ Nonpregnant adult, baseline only. Pregnancy roughly doubles maternal plasma cholesterol; placental demand is on a different order of magnitude and is not captured here. Acute illness, severe stress, and rapid tissue regeneration also raise demand.

7.3 Combined model-estimated transport floor

Model output across a range of plasma TC values:

Plasma TC scenario	LDL surface FC (mg/dL)	HDL surface FC (mg/dL)	Total plasma FC (mg/dL)	Notes
TC 188 (US mean)	~18	~12	~50–55	Línea base
TC 100 (PCSK9-Rx target)	~10	~10	~30	Adequate; well above any structural floor
TC 70 (PCSK9 LOF homozygote)	~4	~9	~17	At or near model floor; empirically tolerated
TC 50 (extreme genetic)	~2	~8	~13	Below any well-validated empirical case

 

Bottom line: the transport model predicts that a nonpregnant adult under baseline conditions can maintain a functional circulating lipoprotein system and meet ~50 mg/day of exogenous tissue demand at plasma total cholesterol on the order of 50–90 mg/dL (sensitivity range 40–110 mg/dL). The chemical form remains roughly 70% esterified and 30% unesterified across this range. The model-floor estimate is in numerical agreement with the plasma TC observed in PCSK9 LOF homozygotes (~50–80 mg/dL), providing independent corroboration from clinical and genetic observation. Modern US adult mean plasma TC of ~188 mg/dL [8] exceeds the model-estimated floor by approximately 2–4×, depending on which sensitivity scenario is used.

7.4 Sensitivity bounds

Assumption varied	Range tested	Effect on transport-floor estimate
Plasma volume	2.5–4.0 L	Inverse scaling; primary effect on absolute mass, secondary on mg/dL
LDL-P at given LDL-C	± 50% of representative	Affects FC component proportionally
Surface FC per LDL particle	300–500	± 15% on FC component
FC per HDL particle	5–15	± 25% on HDL FC component
Net peripheral demand	20–150 mg/day	Adds 5–30 mg/dL margin
Pregnancy / acute illness	—	Model not applicable; demand can rise 2–10×
Combined plausible range (nonpregnant adult, baseline)	—	~40–110 mg/dL plasma TC

8. ApoB Causality and ASCVD Risk

Whether peripheral tissues require circulating cholesterol is a separate question from whether circulating apoB-containing lipoproteins are causally atherogenic. Aleatorización mendeliana across > 50 genetic instruments (LDLR, PCSK9, HMGCR, NPC1L1, APOB, ANGPTL3, LPL, CETP) has established that the lifetime risk of ASCVD tracks cumulative apoB-particle exposure rather than absolute LDL-C concentration alone, with a relación log-lineal between apoB and event risk extending below 20 mg/dL LDL-C. [41][42]

The atherogenic risk imposed by a given circulating cholesterol mass is determined by particle number (apoB count) and residence time, not by whether the cholesterol is required for tissue delivery. The two questions are physiologically orthogonal.

9. Evolutionary and Mechanistic Context

Cholesterol biosynthesis requires 11 molecules of O₂ and roughly 100 ATP equivalents per cholesterol molecule, and involves toxic intermediates. [43][44] This expense is consistent with cholesterol having emerged as eukaryotes adapted to a rising atmospheric oxygen tension; cholesterol both consumes O₂ during synthesis and reduces membrane O₂ permeability, partially functioning as an O₂ sink. [44]

Under the modeling perspective developed in Section 7, the lipoprotein transport system is best interpreted as (i) a vehicle for triglyceride distribution — LDL is a kinetic byproduct of VLDL catabolism — and (ii) a tampón de potencial químico cinético that maintains uniform sterol activity across all extracellular lipid surfaces. [22][23] Under this interpretation, the modern population’s circulating cholesterol concentration is set primarily by hepatic clearance capacity (LDLR density, PCSK9 activity, IDOL activity) rather than by peripheral demand.

10. Conclusions

• Total body cholesterol in an adult is approximately 120–150 g; the plasma compartment of 3–7 g represents 2–5%, not 10–30%, of body content.
• The brain contains ~30–35 g (22–25% of body cholesterol), entirely synthesized locally and isolated from plasma by the blood–brain barrier.
• A representative 22-nm LDL particle contains ~2,200 cholesterol molecules (~1,600 CE + ~600 FC, of which ~400 FC are on the surface). LDL is heterogeneous; these numbers describe a representative reconstruction.
• Plasma cholesterol is ~70% esterified and ~30% free.
• In humans, LDLR-mediated endocytosis carries greater weight than SR-B1 for adrenal and gonadal cholesterol uptake, but SR-B1 remains biologically active.
• Using NMR-consistent lipoprotein particle counts (LDL-P in nmol/L, HDL-P in µmol/L), the model-estimated minimum plasma total cholesterol for a nonpregnant adult under baseline conditions is approximately 50–90 mg/dL (sensitivity 40–110 mg/dL). This is a calculated scenario, not a directly measured human physiological minimum.
• Net daily exogenous cholesterol delivery to peripheral tissues in a nonpregnant adult under baseline conditions is on the order of tens of mg/day, easily met at plasma LDL-C in the 15–30 mg/dL range observed in PCSK9 LOF carriers and in PCSK9-inhibitor trial subjects (FOURIER median 2.2 years, FOURIER-OLE subset median 5.0 additional years), in whom no signal of cholesterol-delivery insufficiency has been reported.
• US adult mean plasma total cholesterol of ~188 mg/dL (NHANES 2017–2018) exceeds the model-estimated transport floor by approximately 2–4×, depending on which sensitivity scenario is used. The surplus is metabolically tolerated, causally tied to ASCVD risk on a per-apoB basis, and not required for any known physiological function in a nonpregnant adult under baseline conditions.

11. Methods Appendix

11.1 Scope

This appendix specifies the equations, parameter values, and assumptions used in the transport-model estimate of Section 7.

11.2 Equations

Plasma cholesterol mass:

M_plasma = TC × V_plasma / 1000   (g)

where TC is in mg/dL and V_plasma is in dL.

Conversion from NMR particle concentration to particles per dL:

N_particles_per_dL = [class-P] × 10⁻⁹ × N_A / 10        (LDL: [LDL-P] in nmol/L)

N_particles_per_dL = [class-P] × 10⁻⁶ × N_A / 10        (HDL: [HDL-P] in µmol/L)

where N_A = 6.022 × 10²³ /mol. The /10 converts L to dL.

Worked example, LDL-P = 1,200 nmol/L:

1,200 × 10⁻⁹ × 6.022 × 10²³ / 10 = 7.23 × 10¹⁶ particles/dL

Worked example, HDL-P = 30 µmol/L:

30 × 10⁻⁶ × 6.022 × 10²³ / 10 = 1.81 × 10¹⁸ particles/dL

Surface FC contribution from one lipoprotein class:

[FC]_class (mg/dL) = N_particles_per_dL × n_FC,class × MW_chol × 1000 / N_A

Worked example, LDL at LDL-C 100 (N = 7.23 × 10¹⁶/dL), 400 surface FC per particle, MW_chol = 386.7 g/mol:

7.23 × 10¹⁶ × 400 × 386.7 × 1000 / 6.022 × 10²³ = ~18.2 mg/dL

Total model-estimated transport floor:

TC_floor ≈ Σ [FC]_class,surface + Σ [FC]_class,core + CE_core,structural + CE_delivery_reserve

11.3 Parameter values used

Parámetro	Central value	Source / basis	Sensitivity range
Plasma volume	3.0 L (= 30 dL)	~42 mL/kg × 70 kg	2.5–4.0 L
LDL-P at LDL-C 100 mg/dL	~1,200 nmol/L (= 7.1 × 10¹⁶ /dL)	NMR LipoProfile data; MESA, Júpiter	600–1,800 nmol/L
HDL-P at HDL-C 50 mg/dL	~30 µmol/L (= 1.8 × 10¹⁸ /dL)	NMR data	20–40 µmol/L
Surface FC per LDL particle	400	Hevonoja 2000 reconstruction [15]	300–500
FC per HDL particle (total)	~10	HDL2/3 composition reviews; calculated from HDL-C / HDL-P at central values	5–15
Net daily peripheral exogenous demand (nonpregnant adult)	~50 mg/day	Composite of adrenal/gonadal/membrane estimates [26][27]	20–150 mg/day
MW cholesterol	386.7 g/mol	Fixed	n/a
Avogadro’s number	6.022 × 10²³ /mol	Fixed	n/a

11.4 Assumptions

The transport-floor calculation depends on assumptions made explicit here:

• The nonpregnant adult is at metabolic steady state under baseline conditions (no pregnancy, no acute illness, no rapid tissue regeneration).
• Plasma volume is taken as a single representative value rather than individualized.
• Particle counts scale approximately linearly with class cholesterol concentration over the modeled range; this approximation breaks down at extremes.
• Surface FC per LDL is taken from the Hevonoja reconstruction; surface composition varies somewhat with particle size and remodeling state.
• FC per HDL particle reflects mature spherical HDL2/3 composition; nascent discoidal HDL has different per-particle FC content.
• Net peripheral demand is taken as order of tens of mg/day; this aggregates tissue-level values that have wide uncertainty under different endocrine states.
• Lp(a), quilomicrones, and chylomicron remnants are not modeled separately; including them would shift the FC contribution upward by a small amount.
• The model is steady-state and ignores diurnal, posprandial, and seasonal variation.

11.5 What this appendix does not establish

This appendix does not establish a measured human physiological minimum for total cholesterol. It provides a transparent, reproducible transport-model estimate. Direct empirical evidence for the safety of very low plasma LDL-C in humans (PCSK9 LOF carriers; PCSK9-inhibitor trial participants) is presented separately in Section 6.3 and remains the strongest evidence that the model’s predicted low floor is physiologically plausible. The two evidence streams are independent: a transport model and a clinical/genetic observation. They are numerically consistent — both indicate that plasma total cholesterol can fall to ~50–80 mg/dL without identified clinical consequence in a nonpregnant adult — but neither alone is dispositive.

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