Sterol Precursors Research Articles

Corticosteroid Hormone Glucocorticoids and Mineralocorticoid

Glucocorticoids and mineralocorticoid are contributors to the corticosteroid hormone family, synthesized in the adrenal gland from the precursor sterol LDL cholesterol using the intermediate pregnenolone. Cortisol is an indispensable glucocorticoid in humans (in rodents, corticosterone), and aldosterone is an important mineralocorticoid. Cortisol and aldosterone share a time-honored synthesis pathway, are structurally similar, and exhibit a degree of cross-receptor affinity and function. Nevertheless, small variations in structure permit critical variants in physiological functions. Aldosterone classically acts via the mineralocorticoid receptor (MR) to promote sodium transport in the kidney and gut, thereby regulating long-term electrolyte homeostasis and blood stress control. Cortisol, via comparison, is well known for a sizeable range of metabolic and stress-related responses

Identification of squalene epoxidase in triterpenes biosynthesis in Poria cocos by molecular docking and CRISPR-Cas9 gene editing

BackgroundSqualene epoxidase is one of the rate-limiting enzymes in the biosynthetic pathway of membrane sterols and triterpenoids. The enzyme catalyzes the formation of oxidized squalene, which is a common precursor of sterols and triterpenoids.ResultIn this study, the squalene epoxidase gene (PcSE) was evaluated in Poria cocos. Molecular docking between PcSE and squalene was performed and the active amino acids were identified. The sgRNA were designed based on the active site residues. The effect on triterpene synthesis in P. cocos was consistent with the results from ultra-high-performance liquid chromatography-quadruplex time-of-flight-double mass spectrometry (UHPLC-QTOF-MS/MS) analysis. The results showed that deletion of PcSE inhibited triterpene synthesis. In vivo verification of PcSE function was performed using a PEG-mediated protoplast transformation approach.ConclusionThe findings from this study provide a foundation for further studies on heterologous biosynthesis of P. cocos secondary metabolites.

Human Sterols Are Overproduced, Stored and Excreted in Yeasts.

Sterols exert a profound influence on numerous cellular processes, playing a crucial role in both health and disease. However, comprehending the effects of sterol dysfunction on cellular physiology is challenging. Consequently, numerous processes affected by impaired sterol biosynthesis still elude our complete understanding. In this study, we made use of yeast strains that produce cholesterol instead of ergosterol and investigated the cellular response mechanisms on the transcriptome as well as the lipid level. The exchange of ergosterol for cholesterol caused the downregulation of phosphatidylethanolamine and phosphatidylserine and upregulation of phosphatidylinositol and phosphatidylcholine biosynthesis. Additionally, a shift towards polyunsaturated fatty acids was observed. While the sphingolipid levels dropped, the total amounts of sterols and triacylglycerol increased, which resulted in 1.7-fold enlarged lipid droplets in cholesterol-producing yeast cells. In addition to internal storage, cholesterol and its precursors were excreted into the culture supernatant, most likely by the action of ABC transporters Snq2, Pdr12 and Pdr15. Overall, our results demonstrate that, similarly to mammalian cells, the production of non-native sterols and sterol precursors causes lipotoxicity in K. phaffii, mainly due to upregulated sterol biosynthesis, and they highlight the different survival and stress response mechanisms on multiple, integrative levels.

Cloning and functional analysis of 3β-hydroxysteroid dehydrogenase gene involved in biosynthesis of digitoxin

Digitoxin, an important secondary metabolite of Digitalis purpurea, is a commonly used cardiotonic in clinical practice. 3β-Hydroxysteroid dehydrogenase(3βHSD) is a key enzyme involved in the biosynthesis of digitoxin. It belongs to the short-chain dehydrogenase/reductase(SDR) family, playing a role in the biosynthesis of cardiac glycosides by oxidizing and isomerizing the precursor sterol. In this study, two 3βHSD genes were cloned from D. purpurea. The results showed that the open reading frame(ORF) of Dp3βHSD1 was 780 bp, encoding 259 amino acid residues. The ORF of Dp3βHSD2 was 774 bp and encoded 257 residues. Dp3βHSD1/2 had the cofactor binding site TGxxxA/GxG and the catalytic site YxxxK. In vitro experiments confirmed that Dp3βHSD1/2 catalyzed the generation of progesterone from pregnenolone, and Dp3βHSD1 had stronger catalytic capacity than Dp3βHSD2. The expression level of Dp3βHSD1 was much higher than that of Dp3βHSD2 in leaves, and digitoxin was only accumulated in leaves. The results implied that Dp3βHSD1 played a role in the dehydrogenation of pregnenolone to produce progesterone in the biosynthesis of digitoxin. This study provides a reference for further exploring the biosynthetic pathway of cardiac glycosides in D. purpurea.

Effects of Neonatal Hypoxic-Ischemic Injury on Brain Sterol Synthesis and Metabolism.

Neonatal hypoxic-ischemic brain injury (HIBI) results from disruptions to blood supply and oxygen in the perinatal brain. The goal of this study was to measure brain sterol metabolites and plasma oxysterols after injury in a neonatal HIBI mouse model to assess for potential therapeutic targets in the brain biochemistry as well as potential circulating diagnostic biomarkers. Postnatal day 9 CD1-IGS mouse pups were randomized to HIBI induced by carotid artery ligation followed by 30 minutes at 8% oxygen or to sham surgery and normoxia. Brain tissue was collected for sterol analysis by liquid chromatography with tandem mass spectrometry (LC-MS/MS). Plasma was collected for oxysterol analysis by LC-MS/MS. There were minimal changes in brain sterol concentrations in the first 72 hours after HIBI. In severely injured brains, there was a significant increase in desmosterol, 7-DHC, 8-DHC, and cholesterol 24 hours after injury in the ipsilateral tissue. Lanosterol, 24-dehydrolathosterol, and 14-dehydrozymostenol decreased in plasma 24 hours after injury. Severe neonatal HIBI was associated with increased cholesterol and sterol precursors in the cortex at 24 hours after injury. Differences in plasma oxysterols were seen at 24 hours but were not present at 30 minutes after injury, suggesting that these sterol intermediates would be of little value as early diagnostic biomarkers.

Promiscuous CYP87A enzyme activity initiates cardenolide biosynthesis in plants.

Cardenolides are specialized, steroidal metabolites produced in a wide array of plant families1,2. Cardenolides play protective roles in plants, but these molecules, including digoxin from foxglove (Digitalis spp.), are better known for treatment of congenital heart failure, atrial arrhythmia, various cancers and other chronic diseases3-9. However, it is still unknown how plants synthesize 'high-value', complex cardenolide structures from, presumably, a sterol precursor. Here we identify two cytochrome P450, family 87, subfamily A (CYP87A) enzymes that act on both cholesterol and phytosterols (campesterol and β-sitosterol) to form pregnenolone, the first committed step in cardenolide biosynthesis in the two phylogenetically distant plants Digitalis purpurea and Calotropis procera. Arabidopsis plants overexpressing these CYP87A enzymes ectopically accumulated pregnenolone, whereas silencing of CYP87A in D. purpurea leaves by RNA interference resulted in substantial reduction of pregnenolone and cardenolides. Our work uncovers the key entry point to the cardenolide pathway, and expands the toolbox for sustainable production of high-value plant steroids via synthetic biology.

Combinatorial metabolic engineering of Saccharomyces cerevisiae for improved production of 7-dehydrocholesterol

7-Dehydrocholesterol (7-DHC), a key pharmaceutical intermediate in the production of vitamin D3, has a wide range of applications. To explore fermentative synthesis of 7-DHC, a 7-DHC-producing Saccharomyces cerevisiae strain was constructed by blocking the competitive pathway, eliminating rate-limiting steps, altering global regulation, and pathway compartmentalization. After blocking the competitive pathway by disrupting ERG5 and ERG6 and introducing DHCR24 from Gallus gallus, S. cerevisiae produced 139.72 mg/L (17.04 mg/g dry cell weight, hereafter abbreviated as DCW) 7-DHC. Subsequent alteration of global regulation by deleting ROX1 and overexpressing UPC2-1 increased 7-DHC production to 217.68 mg/L (37.56 mg/g DCW). To remove the accumulated squalene, the post-squalene pathway was strengthened by co-overexpression of PGAL1-driven ERG11 and PGAL10-driven ERG1, which improved 7-DHC titer and yield to 281.73 mg/L and 46.78 mg/g DCW, respectively, and reduced squalene content by 90.12%. We surmised that the sterol precursors in the plasma membrane and peroxisomes may not be accessible to the pathway enzymes, thus we re-localized DHCR24p and Erg2p-GGGGS-Erg3p to the plasma membrane and peroxisomes, boosting 7-DHC production to 357.53 mg/L (63.12 mg/g DCW). Iron supplementation further increased 7-DHC production to 370.68 mg/L in shake flasks and 1.56 g/L in fed-batch fermentation. This study demonstrates the power of global regulation and subcellular relocalization of key enzymes to improve 7-DHC synthesis in yeast.

Sakuranetin protects rice from brown planthopper attack by depleting its beneficial endosymbionts

Plants produce chemical defenses that poison insect herbivores or deter their feeding, but herbivores are also accompanied by microbial endosymbionts crucial for their nutrition, reproduction, and fitness. Hence, plant defenses could target a herbivore's beneficial endosymbionts, but this has not yet been demonstrated. Here, we studied flavonoids that are induced when rice is attacked by a phloem-feeding pest, the brown planthopper (BPH), which harbors beneficial yeast-like symbionts (YLS) essential for insect nutrition, such as by remedying deficiencies in sterols. BPH attack dramatically increased sakuranetin accumulations in leaf sheaths and phloem exudates. Sakuranetin is an antifungal phytoalexin derived from the antibacterial precursor, naringenin, via catalysis of naringenin-O-methyltransferase (NOMT). When added to artificial diets, sakuranetin decreased BPH survivorship, suggesting that it functions as an induced defense. Mutation of NOMT abolished sakuranetin accumulation and increased BPH oviposition and hatching rates. High-throughput amplicon sequencing revealed that BPH fed on sakuranetin-deficient nomt lines were enriched in YLS with only minor changes in the bacterial endosymbionts, compared to those feeding on sakuranetin-rich wild-type (WT) plants. In-vitro feeding of sakuranetin suggested that this flavonoid directly inhibited the growth of YLS. BPH feeding on nomt lines accumulated higher cholesterol levels, which might be attributed to increases in the supply of sterol precursors from the YLS, while nomt lines suffered more damage than WT plants did from BPH herbivory. BPH-elicited accumulation of sakuranetin requires intact jasmonate (JA) signaling. This study reveals that rice uses a JA-induced antifungal flavonoid phytoalexin in defense against BPH by inhibiting its beneficial endosymbionts.

Recent advances in antifungal drug development targeting lanosterol 14α-demethylase (CYP51): A comprehensive review with structural and molecular insights.

Fungal infections are posing serious threat to healthcare system due to emerging resistance among available antifungal agents. Among available antifungal agents in clinical practice, azoles (diazole, 1,2,4-triazole and tetrazole) remained most effective and widely prescribed antifungal agents. Now their associated side effects and emerging resistance pattern raised a need of new and potent antifungal agents. Lanosterol 14α-demethylase (CYP51) is responsible for the oxidative removal of 14α-methyl group of sterol precursors lanosterol and 24(28)-methylene-24,25-dihydrolanosterol in ergosterol biosynthesis hence an essential component of fungal life cycle and prominent target for antifungal drug development. This review will shed light on various azole- as well as non-azoles-based derivatives as potential antifungal agents that target fungal CYP51. Review will provide deep insight about structure activity relationship, pharmacological outcomes, and interactions of derivatives with CYP51 at molecular level. It will help medicinal chemists working on antifungal development in designing more rational, potent, and safer antifungal agents by targeting fungal CYP51 for tackling emerging antifungal drug resistance.

Sterol methyltransferases in uncultured bacteria complicate eukaryotic biomarker interpretations

Sterane molecular fossils are broadly interpreted as eukaryotic biomarkers, although diverse bacteria also produce sterols. Steranes with side-chain methylations can act as more specific biomarkers if their sterol precursors are limited to particular eukaryotes and are absent in bacteria. One such sterane, 24-isopropylcholestane, has been attributed to demosponges and potentially represents the earliest evidence for animals on Earth, but enzymes that methylate sterols to give the 24-isopropyl side-chain remain undiscovered. Here, we show that sterol methyltransferases from both sponges and yet-uncultured bacteria function in vitro and identify three methyltransferases from symbiotic bacteria each capable of sequential methylations resulting in the 24-isopropyl sterol side-chain. We demonstrate that bacteria have the genomic capacity to synthesize side-chain alkylated sterols, and that bacterial symbionts may contribute to 24-isopropyl sterol biosynthesis in demosponges. Together, our results suggest bacteria should not be dismissed as potential contributing sources of side-chain alkylated sterane biomarkers in the rock record.

The landscape of targets and lead molecules for remyelination.

Remyelination, or the restoration of myelin sheaths around axons in the central nervous system, is a multi-stage repair process that remains a major need for millions of patients with multiple sclerosis and other diseases of myelin. Even into adulthood, rodents and humans can generate new myelin-producing oligodendrocytes, leading to the therapeutic hypothesis that enhancing remyelination could lessen disease burden in multiple sclerosis. Multiple labs have used phenotypic screening to identify dozens of drugs that enhance oligodendrocyte formation, and several hit molecules have now advanced to clinical evaluation. Target identification studies have revealed that a large majority of these hits share the ability to inhibit a narrow range of cholesterol pathway enzymes and thereby induce cellular accumulation of specific sterol precursors to cholesterol. This Perspective surveys the recent fruitful intersection of chemical biology and remyelination and suggests multiple approaches toward new targets and lead molecules to promote remyelination.

Plant Host Traits Mediated by Foliar Fungal Symbionts and Secondary Metabolites.

Fungal symbionts living inside plant leaves ("endophytes") can vary from beneficial to parasitic, but the mechanisms by which the fungi affect the plant host phenotype remain poorly understood. Chemical interactions are likely the proximal mechanism of interaction between foliar endophytes and the plant, as individual fungal strains are often exploited for their diverse secondary metabolite production. Here, we go beyond single strains to examine commonalities in how 16 fungal endophytes shift plant phenotypic traits such as growth and physiology, and how those relate to plant metabolomics profiles. We inoculated individual fungi on switchgrass, Panicum virgatum L. This created a limited range of plant growth and physiology (2-370% of fungus-free controls on average), but effects of most fungi overlapped, indicating functional similarities in unstressed conditions. Overall plant metabolomics profiles included almost 2000 metabolites, which were broadly correlated with plant traits across all the fungal treatments. Terpenoid-rich samples were associated with larger, more physiologically active plants and phenolic-rich samples were associated with smaller, less active plants. Only 47 metabolites were enriched in plants inoculated with fungi relative to fungus-free controls, and of these, Lasso regression identified 12 metabolites that explained from 14 to 43% of plant trait variation. Fungal long-chain fatty acids and sterol precursors were positively associated with plant photosynthesis, conductance, and shoot biomass, but negatively associated with survival. The phytohormone gibberellin, in contrast, was negatively associated with plant physiology and biomass. These results can inform ongoing efforts to develop metabolites as crop management tools, either by direct application or via breeding, by identifying how associations with more beneficial components of the microbiome may be affected.

C30 and C31 steranes in Permian fossil conifers Protophyllocladoxylon

Steroids with alkyl groups at C-2 and C-3 are not known yet in any living organism, while 4-methylsteranes are previously thought specific to 4-methylsteroids bio-synthesized by limited types of organisms, such as dinoflagellates, microalgae, and certain bacteria. Here we investigate the occurrence of C30 2α-, 3β-, 4α-methyl-24-ethylcholestanes, C31 3β,24-diethylcholestanes, and 3,4-dimethyl-24-ethylcholestane, which are tentatively identified in fourteen fossil conifer Protophyllocladoxylon trunk samples from the upper Permian Wutonggou and Guodikeng formations in northwest China. In contrast to the paucity of alkyl steranes in the background sediments, abundant C30 4α-methyl-24-ethylcholestanes in fossil conifers from diverse fluvial–lacustrine environments suggest that conifers were the most likely biological origin for the 4-methyl steranes in conifer trunk samples, although origins from associated fungi might also be possible. Alternatively, these C-4 methyl steranes might have possible algal or prokaryotic origins. It is noteworthy that diagenetic methylation or bacterial alkylation at early stages of diagenesis during burial may have caused a re-arrangement of classical 24-ethylsterols that were bio-synthesized by plants to generate C-2 and C-3 alkylated steranes. This study reports the presence of 4-methylsteranes in conifer fossils for the first time, pointing toward a likely origin from higher plants. This study also provides the first report of C-2 and C-3 alkylated steranes in plant fossils, a.llowing for the possibility that plants may produce functionalised sterol precursors of orphan alkylsteranes that are abundant in geological sediments but whose functionalised precursors are not known from any living organisms.

Archaeological reconnaissance at Lake E5 in the Brooks Range, Alaska and implications for the early human biomarker record of Beringia

Biomarker data from two lakes in arctic Alaska suggest the presence of humans as early as 34,000 calendar years ago. During July 2021 we conducted an archaeological reconnaissance of one of these lakes: Lake E5 in the Kuparuk River Valley (northeastern Brooks Range), which formed on pre-Wisconsinan glacial till deposits. Our field reconnaissance entailed (1) examination of areas of high ground-surface visibility around the lake; (2) identification of geological contexts of late Pleistocene age; and (3) excavation of 1-m2 test pits in topographic and geomorphic settings with high potential for human occupation and preservation of archaeological traces of occupation in buried context. Results were unequivocally negative. We found no prehistoric archaeological materials in the lake's basin, from either surface or sampled subsurface contexts. We also found no obvious landforms to target if a search for preserved archaeological contexts continues. The negative results may reflect a false human signal in the biomarker data, possibly due to taphonomic factors (e.g., microbially-mediated degradation of sterol precursors) or low archaeological visibility of a human presence in this setting (i.e., small lake and basin).

Dishevelled localization and function are differentially regulated by structurally distinct sterols

Aberrant cholesterol synthesis, characterized by depletion of cellular cholesterol and accumulation of sterol precursors, is directly linked to a group of rare human diseases exhibiting broad clinical phenotypes and developmental malformations. Despite decreased cholesterol content being shared across these diseases, patients exhibit distinct clinical manifestations associated with specific tissues or systems with varying degrees of phenotypic overlap. This tissue specificity may result from disease‐specific disruption of important critical signaling pathways due to the inability of sterol precursors to structurally compensate for cholesterol. We previously determined that the cholesterol precursor 7‐dehydrocholesterol (7DHC), which accumulates in Smith‐Lemli‐Opitz syndrome, perturbs Dishevelled 2 (DVL2) protein function due to reduced binding affinity of 7DHC to DVL2’s PDZ domain (Postsynaptic density 95, Disc large 1, and Zonular occludens 1 domain) in comparison to cholesterol, resulting in loss of canonical Wnt/β‐catenin signaling (1). We hypothesized that structural differences between cholesterol and alternative sterols will inhibit binding with DVL2 and other PDZ‐domain containing proteins, producing dire cellular consequences and directly affecting Wnt signaling (2). Protein homology modeling and ligand‐protein docking analysis suggested a differential binding affinity and specificity of DVL2 for cholesterol versus alternative sterols. Using PM‐mimetic vesicles incorporating cholesterol versus alternative sterols in liposome/DVL2 pulldowns, we experimentally observed a reduced binding affinity between DVL2 and alternate sterols. Surface plasmon resonance analysis to define the kinetics of protein‐sterol interaction corroborates in silicomodeling and pulldowns. Our data suggests orientation of the beta‐ and alpha‐sterol face within the DVL2‐PDZ domain binding pocket is predictive of DVL2‐sterol interaction. At the cellular level, we have also observed disruption of DVL2‐sterol binding shifts the subcellular localization of DVL2 from the plasma membrane to the nucleus. Increased nuclear DVL2 promotes non‐canonical WNT signaling and DVL2 protein‐protein binding with nuclear factors. Our work suggests that disrupted sterol homeostasis broadly impacts cellular signaling in a sterol‐specific and pathway‐specific manner. Defining the structural and biochemical requirements for sterol interactions with DVL2 and other cholesterol‐binding proteins will help define the critical role sterol homeostasis plays in human health.(1)Francis KR et al, Nature medicine. 2016;22(4):388‐96.(2) Sheng R et al, Nature communications. 2012;3:1249.

Effective Parameters Controlling Sterol Transfer: A Time-Resolved Small-Angle Neutron Scattering Study.

Though cholesterol is the most prevalent and essential sterol in mammalian cellular membranes, its precursors, post-synthesis cholesterol products, as well as its oxidized derivatives play many other important physiological roles. Using a non-invasive in situ technique, time-resolved small angle neutron scattering, we report on the rate of membrane desorption and corresponding activation energy for this process for a series of sterol precursors and post-synthesis cholesterol products that vary from cholesterol by the number and position of double bonds in B ring of cholesterol's steroid core. In addition, we report on sterols that have oxidation modifications in ring A and ring B of the steroid core. We find that sterols that differ in position or the number of double bonds in ring B have similar time and energy characteristics, while oxysterols have faster transfer rates and lower activation energies than cholesterol in a manner generally consistent with known sterol characteristics, like Log P, the n-octanol/water partitioning coefficient. We find, however, that membrane/water partitioning which is dependent on lipid-sterol interactions is a better predictor, shown by the correlation of the sterols' tilt modulus with both the desorption rates and activation energy.

Identification of oxidosqualene cyclases associated with saponin biosynthesis from Astragalus membranaceus reveals a conserved motif important for catalytic function

IntroductionTriterpenoids and saponins have a broad range of pharmacological activities. Unlike most legumes which contain mainly oleanane-type scaffold, Astragalus membranaceus contains not only oleanane-type but also cycloartane-type saponins, for which the biosynthetic pathways are unknown. ObjectivesThis work aims to study the function and catalytic mechanism of oxidosqualene cyclases (OSCs), one of the most important enzymes in triterpenoid biosynthesis, in A. membranaceus. MethodsTwo OSC genes, AmOSC2 and AmOSC3, were cloned from A. membranaceus. Their functions were studied by heterologous expression in tobacco and yeast, together with in vivo transient expression and virus-induced gene silencing. Site-directed mutagenesis and molecular docking were used to explain the catalytic mechanism for the conserved motif. ResultsAmOSC2 is a β-amyrin synthase which showed higher expression levels in underground parts. It is associated with the production of β-amyrin and soyasaponins (oleanane-type) in vivo. AmOSC3 is a cycloartenol synthase expressed in both aerial and underground parts. It is related to the synthesis of astragalosides (cycloartane-type) in the roots, and to the synthesis of cycloartenol as a plant sterol precursor. From AmOSC2/3, conserved triad motifs VFM/VFN were discovered for β-amyrin/cycloartenol synthases, respectively. The motif is a critical determinant of yield as proved by 10 variants from different OSCs, where the variant containing the conserved motif increased the yield by up to 12.8-fold. Molecular docking and mutagenesis revealed that Val, Phe and Met residues acted together to stabilize the substrate, and the cation-π interactions from Phe played the major role. ConclusionThe study provides insights into the biogenic origin of oleanane-type and cycloartane-type triterpenoids in Astragalus membranaceus. The conserved motif offers new opportunities for OSC engineering.

The Plasma Distribution of Non-cholesterol Sterol Precursors and Products of Cholesterol Synthesis and Phytosterols Depend on HDL Concentration.

Non-cholesterol sterols are transported in plasma lipoproteins and are consequently important in cholesterol metabolism. We investigated the distribution of non-cholesterol sterol precursors of cholesterol synthesis (NCSPCS), oxysterols, and phytosterols in lipoproteins of healthy subjects differing according to HDL-Cholesterol (HDL-C) plasma levels. Elevated NCSPCS (desmosterol, lathosterol) in the High HDL group suggests that HDL exports these sterols from cells, but not the cholesterol metabolite 24-OHC which was higher in the Low HDL group than in the High HDL group. 27-hydroxycholesterol (27OH-C) plasma levels did not differ between groups. Percentage of NCSPCS and phytosterols predominates in LDL, but did not differ between groups. Thirty percent of desmosterol and lathosterol are present in HDL, with the High HDL group carrying higher percentage of these sterols. A high percentage of campesterol and sitosterol in HDL suggests that phytosterols are absorbed by enterocytes, and that HDL could be a marker of the ABCA1/ApoA1 intestinal activity.

Plasma lathosterol measures rates of cholesterol synthesis and efficiency of dietary phytosterols in reducing the plasma cholesterol concentration

Because the plasma campesterol/cholesterol ratio does not differ between groups that absorb different amounts of cholesterol, the authors investigated whether the plasma Phytosterols (PS) relate to the body's cholesterol synthesis rate measured as non-cholesterol sterol precursors (lathosterol). The authors studied38non-obese volunteers (58±12years; Low-Density Lipoprotein Cholesterol ‒ LDL-C≥ 130mg/dL) randomly assigned to consume 400mL/day of soy milk (Control phase) or soy milk+PS (1.6 g/day) forfourweeks in a double-blind, cross-over study. PS and lathosterol were measured in plasma by gas chromatography coupled to mass spectrophotometry. PS treatment reduced plasma total cholesterol concentration (-5.5%, p<0.001), LDL-C (-7.6%, p<0.001), triglycerides (-13.6%, p<0.0085), and apolipoprotein B (apoB) (-6.3%, p<0.008), without changing high density lipoprotein cholesterol (HDL-C concentration), but plasma lathosterol, campesterol and sitosterol expressed per plasma cholesterol increased. The lathosterol-to-cholesterol plasma ratio predicted the plasma cholesterol response to PS feeding. The highest plasma lathosterol concentration during the control phase was associated with a lack of response of plasma cholesterol during the PS treatment period. Consequently, cholesterol synthesis in non-responders to dietary PS being elevated in the control phase indicates these cases resist to further synthesis rise, whereas responders to dietary PS, having in the control phase synthesis values lower than non-responders, expand synthesis on alimentary PS. Responders absorb more PS than non-responders, likely resulting from responders delivering into the intestinal lumen less endogenous cholesterol than non-responders do, thus facilitating greater intestinal absorption of PS shown as increased plasma PS concentration.

New therapeutic agents marketed in 2020: Part 2

New therapeutic agents marketed in 2020: Part 2