Phospholipid molecular species influence crystal habits and transition sequences of metastable intermediates during cholesterol crystallization from bile salt-rich model bile.

Konikoff, F.M.; Cohen, David E.; Carey, Martin C.

doi:10.1016/s0022-2275(20)40128-2

Cited by 59 publications

(13 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As a result, gallstones are spontaneously formed in ABCB4 KO mice on chow, as evidenced by a systematic microscopic and physical-chemical analysis of the biliary and gallstone phenotypes. These studies identify needle-like “anhydrous” cholesterol crystals and gallstone formation as an important feature of ABCB4 KO mice [ 105 ], and these exciting findings further confirm predictions from in vitro studies of model bile with low phospholipid/bile acid ratios that are similar to the lipid composition of gallbladder bile of ABCB4 KO mice [ 24 , 106 , 107 ]. More importantly, these phenotypic findings in ABCB4 KO mice even on chow are in agreement with the hepatobiliary observations of ABCB4 mutations in patients with LPAC.…”

Section: Role Of Abcb4 In the Pathogenesis Of Low Phospholipid-associ...supporting

confidence: 57%

“…In agreement with this paradigm, ABCB4 deficiency can significantly inhibit hepatic secretion of biliary phospholipids, thereby leading to a dramatic decrease in phospholipid concentrations in bile [ 82 , 83 , 84 ]. As a result, the solubility of cholesterol in bile is markedly reduced, allowing for rapid cholesterol nucleation and crystallization for the formation of solid needle-like cholesterol crystals in the bile ducts and gallbladder of ABCB4 KO mice [ 105 ], as well as in model bile with low phospholipid concentrations [ 24 , 106 , 107 ].…”

Section: Role Of Abcb4 In the Pathogenesis Of Low Phospholipid-associ...mentioning

confidence: 99%

“…In early in vitro studies of cholesterol nucleation and crystallization using a series of model bile systems, needle-like, arc-like, and filamentous cholesterol crystals have been identified in bile with low phospholipid/bile acid ratios, and they are found to be apparently “anhydrous” cholesterol crystals that subsequently evolve into plate-like cholesterol monohydrate crystals through a series of intermediates [ 24 , 106 , 107 ]. More importantly, similar nucleation and crystallization of putative “anhydrous” cholesterol is also found in phospholipid-deficient gallbladder bile of ABCB4 KO mice even on chow [ 105 ].…”

Section: Role Of Abcb4 In the Pathogenesis Of Low Phospholipid-associ...mentioning

confidence: 99%

See 2 more Smart Citations

Genetic Analysis of ABCB4 Mutations and Variants Related to the Pathogenesis and Pathophysiology of Low Phospholipid-Associated Cholelithiasis

Wang

Portincasa

Liu

et al. 2022

Genes

View full text Add to dashboard Cite

Clinical studies have revealed that the ABCB4 gene encodes the phospholipid transporter on the canalicular membrane of hepatocytes, and its mutations and variants are the genetic basis of low phospholipid-associated cholelithiasis (LPAC), a rare type of gallstone disease caused by a single-gene mutation or variation. The main features of LPAC include a reduction or deficiency of phospholipids in bile, symptomatic cholelithiasis at <40 years of age, intrahepatic sludge and microlithiasis, mild chronic cholestasis, a high cholesterol/phospholipid ratio in bile, and recurrence of biliary symptoms after cholecystectomy. Needle-like cholesterol crystals, putatively “anhydrous” cholesterol crystallization at low phospholipid concentrations in model and native bile, are characterized in ABCB4 knockout mice, a unique animal model for LPAC. Gallbladder bile with only trace amounts of phospholipids in these mice is supersaturated with cholesterol, with lipid composition plotting in the left two-phase zone of the ternary phase diagram, consistent with “anhydrous” cholesterol crystallization. In this review, we summarize the molecular biology and physiological functions of ABCB4 and comprehensively discuss the latest advances in the genetic analysis of ABCB4 mutations and variations and their roles in the pathogenesis and pathophysiology of LPAC in humans, based on the results from clinical studies and mouse experiments. To date, approximately 158 distinct LPAC-causing ABCB4 mutations and variants in humans have been reported in the literature, indicating that it is a monogenic risk factor for LPAC. The elucidation of the ABCB4 function in the liver, the identification of ABCB4 mutations and variants in LPAC patients, and the exploration of gene therapy for ABCB4 deficiency in animal models can help us to better understand the cellular, molecular, and genetic mechanisms underlying the onset of the disease, and will pave the way for early diagnosis and prevention of susceptible subjects and effective intervention for LPAC in patients.

show abstract

Section: Role Of Abcb4 In the Pathogenesis Of Low Phospholipid-associ...supporting

confidence: 57%

Section: Role Of Abcb4 In the Pathogenesis Of Low Phospholipid-associ...mentioning

confidence: 99%

Section: Role Of Abcb4 In the Pathogenesis Of Low Phospholipid-associ...mentioning

confidence: 99%

See 1 more Smart Citation

Genetic Analysis of ABCB4 Mutations and Variants Related to the Pathogenesis and Pathophysiology of Low Phospholipid-Associated Cholelithiasis

Wang

Portincasa

Liu

et al. 2022

Genes

View full text Add to dashboard Cite

show abstract

“…Time-lapse microscopic study also revealed that CH crystals do not always nucleate plate-like crystals in supersaturated MB systems within physiological lipid compositions, and that lecithin hydrophobicity modulates this process. In dilute bile-salt-rich systems, Konikoff et al have demonstrated that biliary CH does not nucleate classic monohydrate plates, and that lecithin molecular species may affect crystal habit [6,19]. Thus, its physiological relevancy was determined in the present study.…”

Section: The Degree Of Hydrophobicity Of Various Lecithin Species By Hplcmentioning

confidence: 78%

Lecithin hydrophobicity modulates the process of cholesterol crystal nucleation and growth in supersaturated model bile systems

Ochi

Tazuma²,

Kajiyama

1996

Biochemical Journal

View full text Add to dashboard Cite

The present study was performed to determine whether the degree of lecithin hydrophobicity regulates bile metastability and, therefore, affects the process of cholesterol crystallization. Supersaturated model bile (MB) solutions were prepared with an identical composition on a molar basis (taurocholate/lecithin/cholesterol, 73:19.5:7.5; total lipid concentration 9 g/dl) except for the lecithin species; egg yolk phosphatidylcholine, soybean phosphatidylcholine, 1-palmitoyl-2-linoleoyl-sn-phosphatidylcholine, dilinoleoyl phosphatidylcholine and dipalmitoyl phosphatidylcholine. Each MB solution was incubated and sequentially examined. Video-enhanced contrast microscopy demonstrated that the rate of vesicular aggregation and fusion correlated with the degree of lecithin hydrophobicity, and that the rate of cholesterol crystal nucleation correlated with the degree of lecithin hydrophilicity. In MBs containing less hydrophobic lecithin, needle-like crystals developed and transformed into mature plate-like crystals, whereas classical plate-like crystals were consistently observed in MBs composed of hydrophobic lecithin. Laser-diffraction particle size analysis demonstrated that the increase in lecithin hydrophobicity enlarged the vesicle dimension, enhancing its cholesterol-holding capacity. Correlation between vesicular cholesterol packing density and lecithin hydrophobicity suggests that the process of bile cholesterol nucleation and growth is regulated, in part, by acyl chain unsaturation in lecithin. Since the composition of biliary lecithins is responsive to dietary manipulations, this study provides new insights into the prevention of cholesterol gallstones.

show abstract

“…The rate of the transformation between the polymorphs depends on the phospholipid environment. (22,43) Thus, as an example, only macroscopic 3D triclinic crystals are observed associated with sphingomyelin-containing mixed bilayers, whereas the initial monoclinic crystals are retained and developed when they form from DPPC-containing mixed bilayers. (22) Monoclinic helical crystals formed from solutions with bile acids are also relatively long-lived, before transformation to the more stable triclinic polymorph.…”

Section: Resultsmentioning

confidence: 99%

Polymorphism, Structure, and Nucleation of Cholesterol.H2O at Aqueous Interfaces and in Pathological Media: Revisited from a Computational Perspective

Shepelenko

Hirsch

Varsano

et al. 2021

Preprint

View full text Add to dashboard Cite

We revisit the important issues of polymorphism, structure, and nucleation of cholesterol monohydrate, using first principles calculations based on dispersion-augmented density functional theory. For the lesser known monoclinic polymorph, we obtain a new, fully extended H-bonded network, comprising the sterol hydroxyl groups and water molecules in a structure akin to that of hexagonal ice. We show that the energy of the monoclinic and triclinic polymorphs is similar, strongly suggesting that kinetic and environmental effects play a significant role in determining polymorph nucleation. Furthermore, we find evidence in support of various O-H…O bonding motifs, in both polymorphs, that may result in structural disorder. We then rationalize what we believe is a single-crystal to single-crystal transformation of the monoclinic form on increased interlayer growth beyond that of a single cholesterol bilayer, interleaved by a water bilayer, and show that the ice-like structure is also relevant to the related cholestanol dihydrate (2H2O) crystal. Finally, we posit a possible role for cholesterol esters in the crystallization of cholesterol.H2O in pathological environments, with a composite of a bilayer of cholesteryl palmitate bound epitaxially as a nucleating agent to the monoclinic form of cholesterol.H2O.

show abstract

Phospholipid molecular species influence crystal habits and transition sequences of metastable intermediates during cholesterol crystallization from bile salt-rich model bile.

Cited by 59 publications

References 28 publications

Genetic Analysis of ABCB4 Mutations and Variants Related to the Pathogenesis and Pathophysiology of Low Phospholipid-Associated Cholelithiasis

Genetic Analysis of ABCB4 Mutations and Variants Related to the Pathogenesis and Pathophysiology of Low Phospholipid-Associated Cholelithiasis

Lecithin hydrophobicity modulates the process of cholesterol crystal nucleation and growth in supersaturated model bile systems

Polymorphism, Structure, and Nucleation of Cholesterol.H2O at Aqueous Interfaces and in Pathological Media: Revisited from a Computational Perspective

Contact Info

Product

Resources

About