| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Cholesterol and bile acid dynamics: comparative aspects Lutton, C. (1990), Reprod Nutr Dev 30(2): 145-60. Abstract: While the cholesterol concentration in a given tissue is similar in the rat, pig or man, the relative importance of the processes regulating the input (absorption and synthesis) and output (faecal cholesterol and bile acid excretions) of the cholesterol system is very different from one species to another. The rat, whose cholesterolaemia does not significantly increase after cholesterol addition to the diet ("hyporesponding" animal), successfully adapts its bile acid biosynthesis to variations in cholesterol input. This process accounts for 80 to 85% of cholesterol output, faecal cholesterol excretion being a minor process. The latter results from a low liver cholesterol secretion in the bile due to the low hydrophobicity of its main bile acids. Furthermore, in this animal a high intestinal synthesis of cholesterol and apolipoproteins (particularly B48) is observed. The latter are secreted as very light lipoproteins (chylomicrons and VLDL) with a faster plasma turnover than the VLDL (apoB100, E.) secreted by the liver. The "remnants" of rat VLDL are essentially very rapidly taken up by the liver; their interplasmatic transformation pathway into IDL and LDL is not very significant (less than or equal to 10%). Man, who has a more significant hypercholesterolaemia after exogenous cholesterol ingestion ("hyperresponding" subject) seems to have a less modulable capacity for transforming cholesterol into bile acids. This process accounts for only 50% of cholesterol output, faecal cholesterol excretion being quantitatively just as significant. Cholesterol concentration and the cholesterol/bile acid ratio are much higher in human than in rat bile, the main bile acids being more hydrophobic. While both the intestine and liver contribute to cholesterogenesis, the relative importance of the latter is probably greater in man than in the rat. Moreover, a larger fraction of plasma VLDL is transformed into IDL and LDL, the latter representing the main plasma cholesterol carrier. Determining whether the differences between the biodynamics of cholesterol processes in the rat and in man can be generalised to mammals with low or high sensitivities to hypercholesterolaemia and atherosclerosis seems to be a fundamental research objective for the next few years. |
| Cholesterol and bile acid metabolism after selective portal vein ligation Makino, I., K. Chijiiwa, et al. (1997), J Surg Res 68(2): 91-8. Abstract: AIM: To examine the regulatory effect of bile acid level on bile acid synthesis in the liver. METHODS: The portal branch perfusing left lateral and median lobes of the liver was ligated in rats and the activities of hepatic microsomal cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme of bile acid synthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, and intrahepatic concentrations of cholesterol and bile acids were determined in the liver lobes deprived of and supplied with portal blood on Days 0, 1, 2, 4, and 7 after selective portal vein ligation (SPVL). RESULTS: In the portal vein (PV)-ligated lobes, liver weight decreased, hepatic cholesterol concentration was unchanged, and microsomal cholesterol concentration increased after SPVL. In the PV-nonligated lobes, liver weight increased, hepatic cholesterol concentration increased, and microsomal cholesterol concentration was unchanged. There were no significant differences in the activities of HMG-CoA reductase and cholesterol 7 alpha-hydroxylase among the PV-ligated and PV-nonligated lobes and the sham-operated controls. Intrahepatic bile acid level increased significantly in the PV-nonligated lobes for 4 days after SPVL, whereas those were essentially constant in the PV-ligated and the sham-operated control liver. Despite significant changes in the concentrations of intrahepatic cholesterol and bile acid, no significant correlations were observed between these concentrations and the activities of cholesterol 7 alpha-hydroxylase. CONCLUSIONS: SPVL causes atrophy and hypertrophy of the PV-ligated and nonligated liver lobes, respectively, without any significant changes in cholesterol and bile acid synthesis. Intrahepatic concentrations of bile acids and cholesterol have no regulatory effect on cholesterol 7 alpha-hydroxylase activity in the SPVL rat model. |
| Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha Peet, D. J., S. D. Turley, et al. (1998), Cell 93(5): 693-704. Abstract: We demonstrate that mice lacking the oxysterol receptor, LXR alpha, lose their ability to respond normally to dietary cholesterol and are unable to tolerate any amount of cholesterol in excess of that which they synthesize de novo. When fed diets containing cholesterol, LXR alpha (-/-) mice fail to induce transcription of the gene encoding cholesterol 7alpha-hydroxylase (Cyp7a), the rate-limiting enzyme in bile acid synthesis. This defect is associated with a rapid accumulation of large amounts of cholesterol in the liver that eventually leads to impaired hepatic function. The regulation of several other crucial lipid metabolizing genes is also altered in LXR alpha (-/-) mice. These results demonstrate the existence of a physiologically significant feed-forward regulatory pathway for sterol metabolism and establish the role of LXR alpha as the major sensor of dietary cholesterol. |
| Cholesterol and bile acid metabolism in cultures of primary rat bile ductular epithelial cells Hylemon, P. B., P. M. Bohdan, et al. (1990), Hepatology 11(6): 982-8. Abstract: The role of hepatocytes in bile acid and cholesterol metabolism has been extensively studied. By contrast, nothing is known about the role of bile ductular epithelial cells in cholesterol and bile acid metabolism. The purpose of the current studies was to establish whether bile ductular epithelial cells synthesize cholesterol, bile acids or both and to determine whether these cells are capable of metabolizing (hydroxylating, conjugating) bile acids. Bile ductular epithelial cells were isolated from rat liver after ligation of the common bile duct for 6 to 8 wk. Bile ductular epithelial cells were essentially free (greater than 99%) of hepatocytes and were histochemically positive (greater than 80%) for gamma-glutamyl transpeptidase activity. Cholestatic hepatocytes were simultaneously isolated and characterized with regard to their ability to synthesize and metabolize bile acids. Incubation of bile ductular epithelial cells with 14C-acetate resulted in rapid labeling of cellular cholesterol, suggesting that these cells have a complete cholesterol biosynthetic pathway. The addition of 4-14C-cholesterol to bile ductular epithelial cells did not lead to detectable synthesis of 14C-bile acids. 24-14C-Cholic acid, 24-14C-deoxycholic acid, 24-14C-lithocholic acid and 3H-ursodeoxycholic acid were individually added to bile ductular epithelial cells and incubated for 24 or 48 hr. Bile acid metabolites were extracted and separated by C-18 reverse-phase high-performance liquid chromatography or thin-layer chromatography. Bile ductular epithelial cells conjugated deoxycholic acid, ursodeoxycholic acid and lithocholic acid to glycine and taurine. Surprisingly, no conjugation of cholic acid was detected. Conjugated lithocholic acid was further metabolized to highly polar metabolite(s), possibly beta-muricholic acid.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Cholesterol and bile acid replacement therapy in children and adults with Smith-Lemli-Opitz (SLO/RSH) syndrome Nwokoro, N. A. and J. J. Mulvihill (1997), Am J Med Genet 68(3): 315-21. Abstract: Tint et al. N Engl J Med 1994, 330:107-113, working with blood samples from the Smith-Lemli-Opitz syndrome (SLOS) patients of Irons and Elias showed the biochemical basis of this disorder to be a cholesterol biosynthesis defect Irons et al., Lancet, 1993, 341:1414. Based on this finding, clinical protocols for cholesterol and bile acid replacement therapy were established in a few centers including the University of Pittsburgh. We report our experience with bile acid and/or cholesterol replacement therapy in six patients with SLOS, now aged 3-27 years, with a confirmed biochemical diagnosis. Levels of plasma cholesterol and 7-dehydrocholesterol were correlated with periodic clinical evaluations over 8-27 months of therapy. There was a marked improvement in the growth of all the children. There was also an increase in the plasma cholesterol level in all the children and an overall increase in their percent sterol as cholesterol. Subjective improvement was also noted in their development. Although there was no significant change in the plasma cholesterol level of the older patients, there was a marked improvement in their behavior and in their quality of life. |
| Cholesterol and bile acids regulate cholesterol 7 alpha-hydroxylase expression at the transcriptional level in culture and in transgenic mice Ramirez, M. I., D. Karaoglu, et al. (1994), Mol Cell Biol 14(4): 2809-21. Abstract: Cholesterol 7 alpha-hydroxylase (7 alpha-hydroxylase) is the rate-limiting enzyme in bile acid biosynthesis. It is subject to a feedback control, whereby high levels of bile acids suppress its activity, and cholesterol exerts a positive control. It has been suggested that posttranscriptional control plays a major part in that regulation. We have studied the mechanisms by which cholesterol and bile acids regulate expression of the 7 alpha-hydroxylase gene and found it to be solely at the transcriptional level by using two different approaches. First, using a tissue culture system, we localized a liver-specific enhancer located 7 kb upstream of the transcriptional initiation site. We also showed that low-density lipoprotein mediates transcriptional activation of chimeric genes, containing either the 7 alpha-hydroxylase or the albumin enhancer in front of the 7 alpha-hydroxylase proximal promoter, to the same extent as the in vivo cholesterol-mediated regulation of 7 alpha-hydroxylase mRNA. In a second approach, using transgenic mice, we have found that expression of an albumin enhancer-7 alpha-hydroxylase-lacZ fusion gene is restricted to the liver and is regulated by cholesterol and bile acids in a manner quantitatively similar to that of the endogenous gene. We also found, that a liver-specific enhancer is necessary for expression of the rat 7 alpha-hydroxylase gene, in agreement with the tissue culture experiments. Together, these results demonstrate that cholesterol and bile acids regulate the expression of the 7 alpha-hydroxylase gene solely at the transcriptional level. |
| Cholesterol and bile acids regulate xenosensor signaling in drug-mediated induction of cytochromes P450 Handschin, C., M. Podvinec, et al. (2002), J Biol Chem 277(33): 29561-7. Abstract: Cytochromes P450 (CYP) constitute the major enzymatic system for metabolism of xenobiotics. Here we demonstrate that transcriptional activation of CYPs by the drug-sensing nuclear receptors pregnane X receptor, constitutive androstane receptor, and the chicken xenobiotic receptor (CXR) can be modulated by endogenous cholesterol and bile acids. Bile acids induce the chicken drug-activated CYP2H1 via CXR, whereas the hydroxylated metabolites of bile acids and oxysterols inhibit drug induction. The cholesterol-sensing liver X receptor competes with CXR, pregnane X receptor, or constitutive androstane receptor for regulation of drug-responsive enhancers from chicken CYP2H1, human CYP3A4, or human CYP2B6, respectively. Thus, not only cholesterol 7 alpha-hydroxylase (CYP7A1), but also drug-inducible CYPs, are diametrically affected by these receptors. Our findings reveal new insights into the increasingly complex network of nuclear receptors regulating lipid homeostasis and drug metabolism. |
| Cholesterol and cancer in a population of male civil service workers Baptiste, M. S., P. C. Nasca, et al. (1992), Int J Epidemiol 21(1): 16-22. Abstract: Cancer incidence and mortality were ascertained in a cohort of 1910 male participants of the Albany Cardiovascular Health Center (CVHC). The New York State Cancer Registry, vital records files, CVHC follow-up records, New York State Retirement System files, and New York State Department of Motor Vehicles driver's license files were used. Serum cholesterol measurements as well as values for other exposure variables were obtained from records of medical examinations which began in 1953-1954. The study cohort was divided into two groups, based on initial serum cholesterol measurement (less than or equal to 190 mg/100 ml and less than or equal to 190 mg/100 ml). For total cancers, both incidence and mortality were similar in these groups. For digestive cancer, both incidence and mortality were slightly lower in the less than or equal to 190 mg/100 ml group. The deficit was not statistically significant. For respiratory cancer, relative risk and rate ratio estimates were in the range of 1.4-1.7 for incidence and mortality. The excess risk in the less than or equal to 190 mg/100 ml group was of borderline statistical significance. The association was concentrated in the lowest cholesterol quintile rather than suggesting a strong dose-response relationship. The estimates were not found to be confounded by cigarette smoking, body mass index, education or age. A reduction in the crude rate ratio estimate from 1.5 to 1.2 was observed when early cases were excluded, suggesting that part of the observed excess may be due to preclinical cancer. |
| Cholesterol and cardiovascular disease: basic science Barter, P. (1994), Aust N Z J Med 24(1): 83-8. Abstract: Cholesterol is a normal constituent of blood plasma and of cell membranes in every tissue of the body. It is transported in plasma as a component of lipoproteins. Increased concentrations of specific lipoprotein fractions, namely low density lipoproteins (LDL) and intermediate density lipoproteins (IDL), have been implicated both in vitro and in vivo as causes of atherosclerosis. The mechanism by which these lipoproteins initiate atherosclerosis is unknown, although there is growing evidence that it involves interactions between lipoproteins and cells within the artery wall, setting in train complex, reactions which lead ultimately to the fully developed lesions. |
| Cholesterol and cardiovascular disease: how strong is the evidence? LaRosa, J. C. (1992), Clin Cardiol 15(11 Suppl 3): III2-7; discussion III8-9. Abstract: The relationship between elevated serum cholesterol and cardiovascular disease, specifically coronary heart disease (CHD), has been and continues to be a source of debate in the medical community. Other issues under debate include criteria for screening for elevated cholesterol, criteria for treatment, and whether intervention to lower elevated cholesterol prior to a cardiac event is cost effective. Most physicians believe this latter statement to be true; however, reports of no decrease in overall mortality rates in those without clinical coronary disease in whom aggressive lowering of cholesterol is achieved may have contributed to the lack of consensus on this most important issue. In this presentation the evidence that links cholesterol and CHD is reviewed and it is demonstrated that lowering elevated cholesterol concentrations can improve quality of life and life expectancy. |
| Cholesterol and carotid atherosclerosis in older persons: the Framingham Study O'Leary, D. H., K. M. Anderson, et al. (1992), Ann Epidemiol 2(1-2): 147-53. Abstract: We studied the relationship between extracranial carotid atherosclerosis as measured by high-resolution carotid sonography and serum total cholesterol and high-density-lipoprotein cholesterol (HDL-C) levels which were determined at the time of carotid sonography and 8 years previously in 1189 members of the Framingham cohort, aged 66 to 93 years. Among participants, no carotid disease was found in 30%; 1 to 49% stenosis, in 62%; 50 to 74% stenosis, in 5%; 75 to 99% stenosis, in 2%; and 100% stenosis, in 1%. Total cholesterol measured 8 years prior to the carotid examination showed a strong positive association with the occurrence of stenosis in both men and women. There was no association between concurrently measured cholesterol levels and stenosis for either men or women. For women there was a strong association between both the 8-year HDL-C level and the concurrently measured HDL-C level and the degree of carotid stenosis. For men, neither concurrent nor 8-year HDL-C measurements were significantly related to carotid stenosis. These results suggest that there is a time lag between the observation of an elevated cholesterol level and its expression as an increased degree of carotid atherosclerosis. |
| Cholesterol and carotid stenosis Sheikh, K. (2002), Stroke 33(1): 321-2. |
| Cholesterol and cataracts Cenedella, R. J. (1996), Surv Ophthalmol 40(4): 320-37. Abstract: Inherited defects in enzymes of cholesterol metabolism and use of drugs which inhibit lens cholesterol biosynthesis can be associated with cataracts in animals and man. The basis of this relationship apparently lies in the need of the lens to satisfy its sustained requirement for cholesterol by on-site synthesis, and impairing this synthesis can lead to alteration of lens membrane structure. Lens membrane contains the highest cholesterol content of any known membrane. The Smith-Lemli-Opitz syndrome, mevalonic aciduria, and cerebrotendinous xanthomatosis all involve mutations in enzymes of cholesterol metabolism, and affected patients can develop cataracts. Two established models of rodent cataracts are based on treatment with inhibitors of cholesterol biosynthesis. The long-term ocular safety of the very widely used vastatin class of hypocholesterolemic drugs is controversial. Some vastatins are potent inhibitors of cholesterol biosynthesis by animal lenses, can block cholesterol accumulation by these lenses and can produce cataracts in dogs. Whether these drugs inhibit cholesterol biosynthesis in human lenses at therapeutic doses is unknown. Results of clinical trials of 1-5 years duration in older patient populations indicate high ocular safety. However, considering the slow life-long growth of the lens and its continuing need for cholesterol, longterm safety of the vastatins should perhaps be viewed in units of 10 or 20 years, particularly with younger patients. |
| Cholesterol and caveolae: structural and functional relationships Fielding, C. J. and P. E. Fielding (2000), Biochim Biophys Acta 1529(1-3): 210-22. Abstract: Caveolae are free cholesterol (FC)- and sphingolipid-rich surface microdomains abundant in most peripheral cells. Caveolin, a FC binding protein, is a major structural element of these domains. Caveolae serve as portals to regulate cellular FC homeostasis, possibly via their association with ancillary proteins including scavenger receptor B1. The FC content of caveolae regulates the transmission of both extracellular receptor-mediated and endogenous signal transduction via changes in the composition of caveolin-associated complexes of signaling intermediates. By controlling surface FC content, reporting membrane changes by signal transduction to the nucleus, and regulating signal traffic in response to extracellular stimuli, caveolae exert a multifaceted influence on cell physiology including growth and cell division, adhesion, and hormonal response. Cell surface lipid 'rafts' may assume many of the functions of caveolae in cells with low levels of caveolin. |
| Cholesterol- and caveolin-rich membrane domains are essential for phospholipase A2-dependent EDHF formation Graziani, A., V. Bricko, et al. (2004), Cardiovasc Res 64(2): 234-42. Abstract: OBJECTIVE: Cholesterol-rich membrane domains, which contain the scaffold protein caveolin-1 (Cav-1) (caveolae), represent an important structural element involved in endothelial signal transduction. The present study was designed to investigate the role of these signaling platforms in the generation of endothelial-derived hyperpolarizing factor (EDHF). METHODS: Caveolae were disrupted by cholesterol depletion with methyl-beta-cyclodextrin (MbetaCD 10 mM). MbetaCD-induced modulation of non-nitric oxide-/non-prostanoid-dependent (EDHF)-mediated vasorelaxation was studied in pig coronary arteries. Effects of MbetaCD on endothelial Ca(2+) signaling and phospholipase A(2) (cPLA(2)) activity were determined using fura-2 imaging and measurement of (3)H-arachidonate mobilization in cultured pig aortic endothelial cells (PAEC). Cellular localization of caveolin-1 and phospholipase A(2) was investigated by cell fractionation, and interaction of cPLA(2) with caveolin-1 was tested by immunoprecipitation experiments. RESULTS: MbetaCD inhibited EDHF-mediated relaxations of pig coronary arteries induced by bradykinin (100 nM) or ionomycin (300 nM) but not relaxations induced by the NO donor DEA/NO (1 microM). Exposure of arteries to cholesterol-saturated MbetaCD failed to affect EDHF-mediated relaxations. Cholesterol depletion with MbetaCD did not affect bradykinin or ionomycin-induced Ca(2+) signaling in pig aortic endothelial cells, but was associated with enhanced basal and reduced Ca(2+)-dependent release of arachidonic acid (AA). Cell fractionation experiments indicated targeting of cPLA(2) to low density, caveolin-1 rich membranes and immunoprecipitation experiments demonstrated association of phospholipase A(2) with the scaffold protein of caveolae, caveolin-1. Cholesterol depletion with MbetaCD did not disrupt the interaction between cPLA(2) and caveolin-1 but prevented targeting of cPLA(2) to low density membranes. Exogenous supplementation of arachidonic acid after cholesterol depletion partially restored EHDF responses in pig coronary arteries. CONCLUSION: The integrity of caveolin-1-containing membrane microdomains is prerequisite for arachidonic acid recruitment and EDHF signaling in porcine arteries. |
| Cholesterol and change of diet--a reply Werko, L. (1992), Lakartidningen 89(28-29): 2423, 2426-7. |
| Cholesterol and cholate components of an atherogenic diet induce distinct stages of hepatic inflammatory gene expression Vergnes, L., J. Phan, et al. (2003), J Biol Chem 278(44): 42774-84. Abstract: Atherosclerosis in inbred mouse strains has been widely studied by using an atherogenic (Ath) diet containing cholesterol, cholic acid, and fat, but the effect of these components on gene expression has not been systematically examined. We employed DNA microarrays to interrogate gene expression levels in liver of C57BL/6J mice fed the following five diets: mouse chow, the Ath diet, or modified versions of the Ath diet in which either cholesterol, cholate, or fat were omitted. Dietary cholesterol and cholate produced discrete gene expression patterns. Cholesterol was required for induction of genes involved in acute inflammation, including three genes of the serum amyloid A family, three major histocompatibility class II antigen genes, and various cytokine-related genes. In contrast, cholate induced expression of genes involved in extracellular matrix deposition in hepatic fibrosis, including five collagen family members, collagen-interacting proteins, and connective tissue growth factor. The gene expression findings were confirmed by biochemical measurements showing that cholesterol was required for elevation of circulating serum amyloid A, and cholate was required for accumulation of collagen in the liver. The possibility that these gene expression changes are relevant to atherogenesis in C57BL/6J mice was supported by the observation that the closely related, yet atherosclerosis-resistant, C57BL/6ByJ strain was largely resistant to dietary induction of the inflammatory and fibrotic response genes. These results establish that cholesterol and cholate components of the Ath diet have distinct proatherogenic effects on gene expression and suggest a strategy to study the contribution of acute inflammatory response and fibrogenesis independently through dietary manipulation. |
| Cholesterol and cholestasis: a lesson from the Mdr2 (-/-) mouse Fuchs, M. and E. F. Stange (2001), J Hepatol 34(2): 339-41. |
| Cholesterol and cholesterol esters: host receptors for Pseudomonas aeruginosa adherence Rostand, K. S. and J. D. Esko (1993), J Biol Chem 268(32): 24053-9. Abstract: Bacterial adherence to tissues is a necessary step in infection and results from interactions between surface molecules on the bacteria (adhesins) and plasma membrane receptors on host cells. Using a clinical isolate of Pseudomonas aeruginosa, we have examined the receptors required for adherence to Chinese hamster ovary (CHO) cells. In mutant CHO cell lines and mucin-producing lung epithelial cell lines, adherence did not depend on glycoproteins, glycolipids, or proteoglycans. Treating cells with glutaraldehyde and proteases also did not affect adherence. However, treating cells with ethanol diminished adherence and resulted in removal of factors that would facilitate binding of bacteria when coated on plastic culture plates. These factors were purified by solvent extraction and silica gel chromatography and were identified as cholesterol and cholesterol esters by coelution with authentic standards, gas chromatography, 1H NMR, and mass spectrometry. Bacterial adherence was reduced to wild-type CHO cells treated with Lovastatin and to cholesterol-requiring insect cells grown in cholesterol-deficient medium, suggesting that the bacteria bound to plasma membrane cholesterol. Thus, this clinical isolate of Pseudomonas uses cholesterol and cholesterol esters for adherence. We propose that binding to cholesterol and cholesterol esters may affect the pathogenicity of similar Pseudomonas strains. |
| Cholesterol and cholesterol plus DHA diet-induced gene expression and fatty acid changes in mouse eye and brain Puskas, L. G., E. Bereczki, et al. (2004), Biochimie 86(11): 817-24. Abstract: Both cholesterol and polyunsaturated fatty acid (PUFA) metabolism play an important role in retinal and brain development and function. Dietary intake of cholesterol is accompanied with higher risk of heart disease and was suggested to have a role in the pathogenesis of Alzheimer's disease, while dietary PUFAs were reported to act in an opposite way. The same phenomena could be seen in case of inflammation. These effects are mainly realized through gene expression changes. In the present study, the effects of dietary cholesterol and the combination of cholesterol and fish oil were analyzed on the modulation of fatty acid composition and gene expression in the brain and in the eye. At the transcription level, specific changes could be detected in both tissues among transcription factor genes coding for sterol regulatory element binding proteins, retinoid X receptors and peroxisome proliferator-activated receptors, and different fatty acid binding protein genes by using quantitative real-time PCR. In the eye, cholesterol diet attenuated the positive effects of fish oil on inflammatory gene expression as the combined diet resulted in increased RNAm level of phospholipase A-2, inducible nitric oxide synthase, TNF-alpha, COX-1, COX-2 and cytokine, ICAM-1. This induction was absent in the brain. Complex changes could be also recorded in the fatty acid composition of lipids extracted from eye and brain tissue due to the dietary intervention. One of the most interesting changes was the reduced level of docosahexaenoic acid by cholesterol in the eye. Our results on fatty acid composition and gene expression changes may open up new alleys in understanding the complex roles of cholesterol and PUFAs in normal and pathological visual and brain function. |