A role of phospholipase A2 in cholesterol gallstone pathogenesis is associated with biliary phospholipid species subselection at a site of hepatic excretion

Hattori, Yukio; Tazuma, Susumu; Gunji, Yoshio; Sunami, Yuko; Yasumiba, Shigeyuki; Hyogo, Hideyuki; Nishioka, Toshihiko; Miyake, Hiroaki; Miura, Hiroyuki; Kajihara, Toshiki; Ochi, Hisako; Kajiyama, Goro

doi:10.1016/s0016-5085(98)85083-x

Cited by 7 publications

(8 citation statements)

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“…These findings clearly identify MMP‐9 as an important modulator of cholesterol homeostasis and suggest the existence of MMP‐regulated pathways of bile acid synthesis and cholesterol excretion. This latter notion is supported by earlier research linking PLA 2 activity to gallstone formation, although these earlier studies do not invoke regulation of either PLA 2 activity or biliary cholesterol synthesis by MMPs. Similarly, PLA 2 activity has been linked previously to remodeling of lipoproteins and cardiovascular disease, although these earlier studies focused on group II PLA 2 (PLA2G2A; which is not made by C57BL mice) and lipoprotein lipase, PLA 2 s that do not fit the activity or inhibition profile of the plasma sPLA 2 activity that is elevated in mice deficient in either MMP‐9 (as shown in this paper) or MMP‐2 .…”

Section: Discussionmentioning

confidence: 68%

Novel Role for Matrix Metalloproteinase 9 in Modulation of Cholesterol Metabolism

Hernandez-Anzaldo

Brglez

Hemmeryckx

et al. 2016

JAHA

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BackgroundThe development of atherosclerosis is strongly linked to disorders of cholesterol metabolism. Matrix metalloproteinases (MMPs) are dysregulated in patients and animal models with atherosclerosis. Whether systemic MMP activity influences cholesterol metabolism is unknown.Methods and ResultsWe examined MMP‐9–deficient (Mmp9 −/−) mice and found them to have abnormal lipid gene transcriptional responses to dietary cholesterol supplementation. As opposed to Mmp9 +/+ (wild‐type) mice, Mmp9 −/− mice failed to decrease the hepatic expression of sterol regulatory element binding protein 2 pathway genes, which control hepatic cholesterol biosynthesis and uptake. Furthermore, Mmp9 −/− mice failed to increase the expression of genes encoding the rate‐limiting enzymes in biliary cholesterol excretion (eg, Cyp7a and Cyp27a). In contrast, MMP‐9 deficiency did not impair intestinal cholesterol absorption, as shown by the 14C‐cholesterol and 3H‐sitostanol absorption assay. Similar to our earlier study on Mmp2 −/− mice, we observed that Mmp9 −/− mice had elevated plasma secreted phospholipase A2 activity. Pharmacological inhibition of systemic circulating secreted phospholipase A2 activity (with varespladib) partially normalized the hepatic transcriptional responses to dietary cholesterol in Mmp9 −/− mice. Functional studies with mice deficient in other MMPs suggested an important role for the MMP system, as a whole, in modulation of cholesterol metabolism.ConclusionsOur results show that MMP‐9 modulates cholesterol metabolism, at least in part, through a novel MMP‐9–plasma secreted phospholipase A2 axis that affects the hepatic transcriptional responses to dietary cholesterol. Furthermore, the data suggest that dysregulation of the MMP system can result in metabolic disorder, which could lead to atherosclerosis and coronary heart disease.

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Section: Discussionmentioning

confidence: 68%

Novel Role for Matrix Metalloproteinase 9 in Modulation of Cholesterol Metabolism

Hernandez-Anzaldo

Brglez

Hemmeryckx

et al. 2016

JAHA

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“…Subsequently, the vesicle-related turbidity was estimated by subtraction of the absorbance measured in the presence of sodium taurodeoxycholate at the concentration required to completely dissolve the vesicles from the absorbance in the absence of sodium taurodeoxycholate. Measurements were performed every 24-48 h. The calculation of the crystal growth rate (CGR) was performed by adjusting data plotted to the sigmoidal curve tangent as previously described [6,14,17]. The slope of this linear line was used as the CGR.…”

Section: Vesicle and Cholesterol Crystal (Vcc) And Cholesterol Crystamentioning

confidence: 99%

Less hydrophobic phosphatidylcholine species simplify biliary vesicle morphology, but induce bile metastability with a broad spectrum of crystal forms

2002

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Cholesterol crystallization in bile is affected by phosphatidylcholine (PtdCho) hydrophobicity. The aim of the present study was to determine whether PtdCho species modulate the metastable-labile limit and equilibrium solubility of cholesterol in the micellar phase of bile, thereby altering the distribution of cholesterol to biliary lipid carriers and thus influencing cholesterol crystallization. Supersaturated model bile (with a cholesterol saturation index of 2.0 and a total lipid concentration of 10 g/dl) was prepared with various PtdCho/(bile salt+PtdCho) ratios (0.1-0.5) using egg yolk or soya bean PtdCho. Subsequently, the following features were determined: metastable-labile limit, equilibrium solubility of cholesterol, metastable zone, and cholesterol crystallization process. Less hydrophobic PtdCho species destabilized bile cholesterol to induce rapid crystallization, because of a broad integrated metastable zone, whereas more hydrophobic species stabilized bile cholesterol with a less integrated metastable zone and thus retarded cholesterol crystallization. Cholesterol crystallization was accelerated by a decrease in the PtdCho/(bile salt+PtdCho) ratio, whereas the final nucleated crystal mass was increased by an increase in this ratio. With decreasing hydrophobicity of the PtdCho species, the intermixed micellar/vesicular concentration of bile salts decreased in association with less formation of vesicles and increased formation of micelles, and a variety of crystal forms were detected. In conclusion, PtdCho species directly influenced the cholesterol crystallization process in model bile by remodelling the bile mesophase, and also had an indirect influence by altering the balance between bile salt micelles and vesicles.

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“…The incidence of gallstones is 15% in America, 5.9∼21.9% in Europe, 4∼15% in Asia and 3∼11% in China [5]–[7]. Current research suggests that different types of gallstones have different pathogenesis [8]–[16]. Research on the systematic classification of gallbladder stones may help to reveal the formation mechanism of different types of gallstones.…”

Section: Introductionmentioning

confidence: 99%

The Systematic Classification of Gallbladder Stones

Qiao

Luo

et al. 2013

PLoS ONE

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BackgroundTo develop a method for systematic classification of gallbladder stones, analyze the clinical characteristics of each type of stone and provide a theoretical basis for the study of the formation mechanism of different types of gallbladder stones.MethodologyA total of 807 consecutive patients with gallbladder stones were enrolled and their gallstones were studied. The material composition of gallbladder stones was analyzed using Fourier Transform Infrared spectroscopy and the distribution and microstructure of material components was observed with Scanning Electron Microscopy. The composition and distribution of elements were analyzed by an X-ray energy spectrometer. Gallbladder stones were classified accordingly, and then, gender, age, medical history and BMI of patients with each type of stone were analyzed.Principal FindingsGallbladder stones were classified into 8 types and more than ten subtypes, including cholesterol stones (297), pigment stones (217), calcium carbonate stones (139), phosphate stones (12), calcium stearate stones (9), protein stones (3), cystine stones (1) and mixed stones (129). Mixed stones were those stones with two or more than two kinds of material components and the content of each component was similar. A total of 11 subtypes of mixed stones were found in this study. Patients with cholesterol stones were mainly female between the ages of 30 and 50, with higher BMI and shorter medical history than patients with pigment stones (P<0.05), however, patients with pigment, calcium carbonate, phosphate stones were mainly male between the ages of 40 and 60.ConclusionThe systematic classification of gallbladder stones indicates that different types of stones have different characteristics in terms of the microstructure, elemental composition and distribution, providing an important basis for the mechanistic study of gallbladder stones.

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A role of phospholipase A2 in cholesterol gallstone pathogenesis is associated with biliary phospholipid species subselection at a site of hepatic excretion

Cited by 7 publications

References 0 publications

Novel Role for Matrix Metalloproteinase 9 in Modulation of Cholesterol Metabolism

Novel Role for Matrix Metalloproteinase 9 in Modulation of Cholesterol Metabolism

Less hydrophobic phosphatidylcholine species simplify biliary vesicle morphology, but induce bile metastability with a broad spectrum of crystal forms

The Systematic Classification of Gallbladder Stones

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