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12РОЛЬ ЛИПИДНОГО ОБМЕНА В РАЗВИТИИ БИЛИАРНЫХ ЗАБОЛЕВАНИЙ
Усмонов Элёрбек Илхомович Салахидинов Сарваржон Зайнабидинович Усмонов Хусниддин Кутбинович
Андижанский государственный медицинский институт
На желчевыводящую систему влияет широкий спектр заболеваний, которые часто проявляются сходными клиническими признаками и симптомами. К ним относятся камни в желчном пузыре, острый желчно-каменный холецистит, острый холецистит акакулуса, синдром Мириззи, хронический холецистит, холангит (рецидивирующий пиогенный, первичный склероз, первичный билиарный, аутоиммунный), опасные заболевания желчных протоков, желчи или кисты и другие. Метаболизм также играет роль в развитии этих заболеваний. В этой статье обсуждается роль липидного обмена в развитии заболеваний желчевыводящих путей.
Ключевые слова: билиарная система, холецистит, синдром Мириззи, холангит, гнойный, склероз, аутоиммунный, киста, липидный обмен.
O'T-SAFRO KASALLIKLARINING RIVOJLANISHIDA LIPID METABOLIZMINING
AHAMIYATI
Kasalliklarning xilma-xil spektri o't-safro tizimga ta'sir qiladi, ko'pincha o'xshash klinik belgilar va simptomlar bilan namoyon bo'ladi. Ushbu holatlarga o't toshlari, o'tkir toshli xoletsistit, o'tkir akalkulus xoletsistit, Mirizzi sindromi, surunkali xoletsistit, xolangit (takroriy pyogenik, birlamchi sklerozlash, birlamchi biliar, autoimmun), safro yo'llarining xavfli kasalliklari, o't yo'llarining kistalari va boshqalar kiradi. Ushbu kasalliklarning rivojlanishida moddalar almashinuvi ham o'z ahamiyatiga ega. Ushbu maqolada lipid metabolizmining safro kasalliklarining rivojlanishidagi ahamiyati muhokama qilinadi.
Kalit so'zlar: Safro tizimi, xoletsistit, Mirizzi sindromi, xolangit, pyogenik, sklerozlanish, autoimmun, kista, lipid metabolizmi.
THE ROLE OF LIPID METABOLISM IN THE DEVELOPMENT OF BILIARY DISEASES
A diverse spectrum of diseases affects the biliary system, often presenting with similar clinical signs and symptoms. These conditions include gallstones, acute calculus cholecystitis, acute acalculus cholecystitis, Mirizzi syndrome, chronic cholecystitis, cholangitis (recurrent pyogenic, primary sclerosing, primary biliary, autoimmune), biliary tract malignancies, biliary tract cysts, and others. Metabolism also plays a role in the development of these diseases. This article discusses the role of lipid metabolism in the development of biliary diseases.
Keywords: biliary system, cholecystitis, Mirizzi syndrome, cholangitis, pyogenic, primary sclerosing, autoimmune, cyst, lipid metabolism.
DOI: 10.24411/2181-0443/2020-10102
Introduction: Progression of intensity of lipid disorders in patients with NASH in combination with obesity and BT pathology depends on increase of BMI parameters. The concomitant BT pathology partially influences the parameters of lipid blood spectrum. HDL was equally decreased in all patients with NASH at CNC and CCC relative to patients with
concomitant PCES and HDL level within physiological norm. At NASH in combination with obesity at increase of BMI the DL phenomena more often appear in patients.
Based on the results of a study by a group of scientists, we can see that there is a link between lipid metabolism and the bile system [2]: Defects in the Fanconi anemia (FA) DNA damage-response pathway result in genomic instability, developmental defects, hematopoietic failure, cancer predisposition, and metabolic disorders. The endogenous sources of damage contributing to FA phenotypes and the links between FA and metabolic disease remain poorly understood. Here, using mice lacking the Fancd2 gene, encoding a central FA pathway component, we investigated whether the FA pathway protects against metabolic challenges. Fancd2 -/- and wildtype (WT) mice were fed a standard diet (SD), a diet enriched in fat, cholesterol, and cholic acid (Paigen diet), or a diet enriched in lipid alone (high-fat diet (HFD)). Fancd2 -/- mice developed hepatobiliary disease and exhibited decreased survival when fed a Paigen diet but not a HFD. Male Paigen diet-fed mice lacking Fancd2 had significant biliary hyperplasia, increased serum bile acid concentration, and increased hepatic pathology. In contrast, female mice were similarly impacted by Paigen diet feeding regardless of Fancd2 status. Upon Paigen diet challenge, male Fancd2 -/- mice had altered expression of genes encoding hepatic bile acid transporters and cholesterol and fatty acid metabolism proteins, including Scp2/x, Abcg5/8, Abca1, Ldlr, Srebf1, and Scd-1 Untargeted lipidomic profiling in liver tissue revealed 132 lipid species, including sphingolipids, glycerophospholipids, and glycerolipids, that differed significantly in abundance depending on Fancd2 status in male mice. We conclude that the FA pathway has sex-specific impacts on hepatic lipid and bile acid metabolism, findings that expand the known functions of the FA pathway and may provide mechanistic insight into the metabolic disease predisposition in individuals with FA.
In addition [3] nutritional factors play a key role in the pathogenesis of biliary diseases such as gallstones and pancreaticobiliary maljunction. Gallstones are primarily classified into cholesterol stone and pigment stone according to the major composition. Cholesterol gallstone formation is very likely based upon supersaturated bile formation, and pigment stones are formed in bile rich in bilirubin. Thus, defects of hepatic metabolism of lipids and organic anions lead to biliary stones. Here, the recent understanding of cholesterol gallstone pathogenesis is elaborated. On the other hand, there is another important link of biliary lipid degradation to serious biliary disease, namely pancreaticobiliary maljunction. Lysophosphatidylcholine (lysoPC), a derivative of phosphatidylcholine hydrolysis by phospholipase A2, is a highly abundant bioactive lipid mediator present in circulation as well as in bile. Increases in bile of lysoPC and phospholipase A2 have been reported in pancreaticobiliary maljunction and considered to be the major risk factor for biliary tract cancers. Further, oxidized fatty acids have been established as a potent ligand for G2A, a member of G protein-coupled receptor family that mediates a diverse array of biological processes including cell growth and apoptosis. Thus, both of lysoPC and free fatty acids are supposed to play an important role through G2A in biliary inflammation and carcinogenesis of pancreaticobiliary maljunction. Taken together, nutritional factors, especially lipid compounds, are seemingly crucial in the pathogenesis of biliary diseases, and such a causal relationship is reviewed by mainly authors' previous publications.
Gallstone and lipid metabolism. Epidemiologically, the prevalence of gallstone diseases is known to increase in Western countries including Japan, and biliary stones, common and intrahepatic bile duct stones, are relatively popular in Asia. [4] Gallstones are primarily classified into cholesterol stone and pigment stone according to the major composition. Cholesterol gallstone formation is very likely based upon supersaturated bile formation, and pigment stones are formed in bile rich in bilirubin. Thus, defects of hepatic metabolism of lipids and organic anions lead to biliary stones. Here, cholesterol gallstone
pathogenesis and clinical implication is mainly reviewed. Cholesterol is an insoluble molecule that is critical for cellular structure and function. Homeostasis of this compound is kept by biliary elimination from the liver, where it is catabolized to bile salts for a regulation of pool size. Under physiological circumstances, cholesterol in bile is in a physicochemically stabilized by forming bile salt micelles. However, once defects in such a metabolic regulation occur, bile cholesterol becomes metastable to induce cholesterol crystal nucleation as an initial step for gallstone formation. In general, the sequence of gallstone formation and clinical implication is to be in a step-by-step manner: genetics, defects of biliary lipid metabolism, cholesterol nucleation and crystal growth to macroscopic stone formation, and finally clinical symptoms (Figure 1). Thus, such processes are summarized into two major steps: (i) metabolic abnormalities in the hepatobiliary system and (ii) physical-chemical events in the gallbladder [5].
Metabolic abnormalities in the hepatobiliary system. Lithogenic bile is formed by excess secretion of cholesterol from the liver into bile. Hypersecretion of cholesterol is particularly pronounced in obese people in association with a high prevalence of cholesterol gallstones. Leptin, an adipocytokine produced in adipocytes, enhances biliary lipid secretion, and another adiocytokine, adiponectin could play a rescue role in cholesterol cholelithiasis [6]. Recently, homocystein has been reported to be another factor affecting such a hepatic metabolism and is to be a clinical parameter for lithogenic risk, which is still to be established [7]. Availability of agents for dyslipidemia and future direction. Based upon the understandings of defects of metabolism in gallstone diseases, agents for dyslipidemias are reported in this regard. Taken together, statins are promising for an adjuvant, not to worsen bile cholesterol metastability. [8-11] In contrast, fibrates, a ligand for nuclear receptors, enhance the phospholipid secretion into bile, and cholesterol in vesicles is physicochemically stabilized. [12] Genetics are focused on "gallstone map," but the role of disease genetics is yet to be established. [13] The scientific literature of the past year clarifies underlying mechanism(s) of cholesterol gallstone formation process, especially in the aspects of physiology, physical chemistry, molecular biology, and genetics of biliary lipid metabolism. Collectively, these studies provide tremendous progress in understanding cholesterol gallstone pathogenesis, supplying ideas of future strategies for prevention and/or non-surgical therapeutics, instead for just removing gallbladder, namely cholecystectomy [14].
Figure 1. Cholesterol gallstone formation process.
1. Genetics and defects of lipid metabolism
2. Physical-chemical metastability of bile
3. Cholesterol crystal nucleation
4. Crystal growth to macroscopic stones
5. Clinical symptoms
Biliary components and biliary system damages. Biliary systems are exposed to bile rich in lipids and bile salts under a physiological circumstance. Bile salts are strong detergents and certain lipid molecules such as lysophosphatidylcholine (lysoPC), oxidized fatty acids, are also having a detergent potential. Accordingly, there must be a protective system against such cytotoxic constituents in bile. In principle, biliary carcinogenesis is considered to be related to chronic biliary inflammation and pancreatobiliary reflux and thus, the degradation of biliary lipids, a nutritional factor, is focused on in the light of cytotoxicity and cytoprotection of biliary systems under a certain condition of chronic biliary disorders, such as pancreaticobiliary maljunction [15].
Bile constituents and biliary system damage. Bile consists of cholesterol, phospholipids, and bile salts. Bile salts are composed of various species as well as phospholipids. Our previous reports indicate that hydrophobic bile salts induce cholangiocyte apoptosis through the oxidative stress-mediated mechanism. [16] Cholangiocyte has an absorption system of bile salts (apical sodium-dependent bile salt transporter) and the excess bile salts, which induce apoptosis through death signals, are eliminated through a membrane transporter (multidrug resistance transporterassociated protein 3) in a rodent model, and those molecules are regulated by a nuclear receptor (farnesoid X receptor) as summarized in figure (Figure 6). [17,18] The regulatory system for bile salt trafficking is mediated by nuclear receptors affecting various bile salt transporters expression. In this scenario, the fact that UDCA, a hydrophilic bile salt, and phospholipids such as PC play a role as the rescue system is of pathophysiological importance. [19,20] Similar phenomenon is evident in the gallbladder. [21] Thus, a disruption of these systems is very likely to cause serious biliary damages.
Figure 6. Cholangiocyte apoptosis induced by bile salts: Nuclear receptor and membrane transporters function. Asbt, apical sodiumdependent bile salt transporter; FXR, farnesoid X receptor; Mrp3, multidrug resistance transporter-associated protein 3; PC, phosphatidylcholine.
Degradation of bile lipid and biliary system damages in pancreaticobiliary maljunction. There is an important link of biliary lipid degradation to serious biliary disease, namely pancreaticobiliary maljunction. LysoPC, a derivative of PC hydrolysis by PLA2, is a highly abundant bioactive lipid mediator present in circulation as well as in bile. LysoPC and PLA2 are significantly increased in bile of the patients with pancreaticobiliary maljunction or intrahepatic cholelithiasis, both of which are considered to be major risk factors for biliary tract cancers with undefined etiology. Biliary epithelial cells are continuously exposed to bile, and an increase of biliary lysoPC is suggested to induce biliary cell damages and the subsequent carcinogenesis. In our previous study investigating the influence of lysoPC on HuCCT-1, a human cholangiocellular carcinoma cell line, LysoPC exhibited significant cytotoxicity with induction of apoptosis (unpublished data). Also, an upregulation of Fas receptor messenger RNA (mRNA) in association with increased activities of caspase 8 and 3 is evident. In addition, the upregulation of Bax mRNA expression and the increased activity of caspase 9 suggest that lysoPC-induced apoptosis in biliary systems is mediated through both the extrinsic (death receptor-dependent) and the intrinsic (mitochondria-dependent) signaling pathway. In addition, lysoPC markedly induced mRNA G2A expression in biliary cells, indicating the possibility that lysoPC induced apoptosis in biliary systems through a G2A-mediated (extrinsic and the intrinsic) signaling pathway. The oxidized free fatty acids, a potent ligand for G2A, are produced, following PLA2-mediated hydrolysis of PC to yield lysoPC and free fatty acid. Thus, nutritional factors, especially lipid compounds, play a pathogenic role in biliary diseases. Certainly, there might be cytoprotective systems under physiological circumstances against such cytotoxic constituents, and how to keep such a system from disruption is to be of clinical importance in prevention. A hydrophilic bile salt such as UDCA is a potent agent for protection of hepatobiliary systems against hydrophobic bile salts, toxic lipids, as well as pharmaceutical compounds secreted into bile through "micellar sink" mechanisms [22-25] Conclusion: In summary, the development of biliary disease is directly related to lipid metabolism. The article explains this in detail. The scientific work of several researchers in this regard was discussed. We hope that this article will be the basis for the prevention and treatment of disorders of lipid metabolism in biliary diseases.
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