Effect of cholesterol metabolism on hepatolithiasis

Abstract

Surgical intervention is currently the primary treatment for hepatolithiasis; however, some patients still experience residual stones and high recurrence rates after surgery. Cholesterol metabolism seems to play an important role in hepatolithiasis pathogenesis. A high cholesterol diet is one of the significant reasons for the increasing incidence of hepatolithiasis. Therefore, regular diet and appropriate medical intervention are crucial measures to prevent hepatolithiasis and reduce recurrence rate after surgery. Reducing dietary cholesterol and drugs that increase cholesterol stone solubility are key therapeutic approaches in treating hepatolithiasis. This article discusses the cholesterol metabolic pathways related to the pathogenesis of hepatolithiasis, as well as food intake and targeted therapeutic drugs.

Key Words: Hepatolithiasis; Cholesterol metabolism; High-fat diet; 3-hydroxy-3-methylglutaryl-coenzyme A reductase; Interlobular bile duct

Core Tip: Surgery is the primary treatment for hepatolithiasis. Although surgical methods are effective, increasing incidence and postoperative recurrence have become one of the complications in the diagnosis and treatment of hepatolithiasis. Therefore, understanding cholesterol metabolism and dietary and drug interventions to prevent the occurrence and development of hepatolithiasis are important.

TO THE EDITOR

We read with great interest the recent paper by Motta et al[1]. We would first like to thank the authors for providing a detailed introduction about hepatolithiasis from the aspects of epidemiology, pathophysiology, clinical characteristics, the various classification systems and modern treatment. It is well known that surgery is the main treatment for hepatolithiasis. With improvements in surgeons' skills and the continuous update of equipment, laparoscopic hepatectomy has become the primary surgical method for treating hepatolithiasis due to its advantages, including low blood loss, low blood transfusion rate and short hospital stay. Subsequently, minimally invasive surgery modalities have become widely recognized. In recent years, advanced technologies such as robotic surgical systems and percutaneous transhepatic choledochoscopic lithotomy have achieved more satisfactory treatment results for hepatolithiasis[2-4]. Although surgery has long been the primary treatment method, some patients still suffer from residual stones and a high recurrence rate after surgery. Therefore, it is very important to understand the pathogenesis of intrahepatic bile duct stones and corresponding medical treatment. We have found that cholesterol metabolism plays an important role in the occurrence and development of intrahepatic bile duct stones. Therefore, we would like to further discuss the role of cholesterol metabolism in the pathogenesis of intrahepatic bile duct stones, as well as the diet and drug therapies that affect cholesterol metabolism.

CHOLESTEROL METABOLISM HOMEOSTASIS

Cholesterol homeostasis is achieved by regulating dietary cholesterol intake, liver cholesterol production and transformation. Acetyl coenzyme A (acetyl-CoA) is the direct raw material of cholesterol biosynthesis; cholesterol synthesis goes through five stages, of which 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) is the key rate-limiting enzyme in the first stage. Overexpression HMGCR results in hepatic free cholesterol accumulation and elevates the cholesterol saturation index in bile[5]. Secondly, sterol regulatory element-binding proteins (SREBPs) are key regulatory proteins in cholesterol biosynthesis. When the cellular cholesterol concentration changes, SREBP activity also changes accordingly, thus maintaining cholesterol homeostasis[6,7]. In addition to direct cholesterol synthesis in the liver, cholesterol can also be taken up in the diet through the Niemann-Pick C1 Like 1 (NPC1L1) protein. Alternatively, high density lipoprotein cholesteryl esters are selectively taken up by low-density lipoprotein receptors and scavenger receptor class B, type I[8,9]. Synthesized and ingested cholesterol is transported by apolipoprotein E to cells throughout the body for use. Excess cholesterol in the body is transported back to the liver by high-density lipoprotein (HDL), where it activates liver X receptor (LXR). LXR then forms heterodimers with LXR agonists to activate ATP-binding cassette (ABC) family members, particularly ABCA1, which is responsible for the expulsion of cholesterol into the blood. ABCG5 and ABCG8 excrete cholesterol into the bile[6,10]. At the same time, the remaining excess cholesterol in the liver is catalyzed by cholesterol acyltransferase (ACAT) to produce cholesteryl esters and by cholesterol 7α-hydroxylase to produce bile acids and transported to bile under the action of ABCB11[11].

Most cholesterol is synthesized directly in the liver, and a small part is absorbed through the small intestine mucosa from food (Figure 1). The synthesized cholesterol is not only an important component of cell membranes and plasma lipoproteins, but also a precursor to many steroids that play a role throughout the body. Most unused cholesterol is converted into bile acids and excreted through bile, and a small amount is reduced to coprosterols by intestinal bacteria. Cholesterol maintains a dynamic balance through a complex process, and when cholesterol metabolism is dysfunctional, it can cause damage to the body.

Figure 1 Cholesterol metabolic pathway. Cholesterol is synthesized directly in the liver or taken up by the epithelial cells of the small intestine. Niemann-Pick C1 Like 1 (NPC1 L1) in the small intestine absorbs dietary cholesterol into cells through endocytosis, which is transformed into nascent chylomicrons and then enters the blood. Under the action of high-density lipoprotein (HDL), nascent chylomicrons are transformed into chylomicrons, and then the chylomicrons decompose most of the triglycerides under the action of lipoprotein lipase (LPL), and the rest of the chylomicron remnants are used in the liver. The cholesterol directly produced in the liver is converted into bile acid by CYP7A1 and transported into the bile duct under the action of ABCB11. Some of the cholesterol is formed into cholesterol ester under the action of ACAT. Some of the excess cholesterol enters the bile duct through transport by ABCG5/ABCG8, and some enters the blood through transport by ABCA1. CoA: Coenzyme A; LXR: Liver X receptor.

THE ROLE OF CHOLESTEROL METABOLISM IN HEPATOLITHIASIS

Abnormal cholesterol metabolism induced by gallbladder movement disorders, intestinal flora, genetic factors, sex, age, obesity and other factors may lead to excessive cholesterol accumulation, thus leading to hepatolithiasis[12-15]. When the dynamic balance of cholesterol is upset, excess cholesterol in the liver and gallbladder bile may form stones. Cholesterol in the blood is also associated with a significantly higher risk of hypercholesterolemic vascular disease (atherosclerosis). Understanding the formation of different types of gallstones may help to elucidate the pathogenesis of intrahepatic gallstones. Calcium bilirubin calculi and cholesterol calculi are typical types of intrahepatic bile duct calculi. In addition to calcium bilirubin and a small amount of cholesterol in calcium bilirubin stones, they also contain fatty acids and free bile acids. The presence of these components indicates bacterial involvement, and other studies have also demonstrated that diet and bacterial infection with cholestasis are important influencing factors[16,17]. Unlike calcium bilirubin stones, bacterial infection plays a smaller role in the formation and subsequent progression of intrahepatic cholesterol stones and may arise in the bile duct and interlobular bile duct in a microenvironment with reduced cholesterol-supersaturated bile and apolipoprotein A-1 activity[18,19].

THE ROLE OF CHOLESTEROL METABOLISM IN OTHER DISEASES

In addition to being the main cause of intrahepatic bile duct stone formation, cholesterol metabolism is closely related to other diseases. In a study on cholesterol metabolism, subjects included mild, moderate, severe, and critically ill coronavirus disease 2019 patients. The results showed that severe and critically ill patients had lower levels of HDL cholesterol than moderate and mild patients. This may be because the coronavirus prompts host cells to alter the expression of cholesterol-metabolizing enzymes and metabolites, and the framework structure required for viral replication depends on cholesterol and specific lipid components[20]. In addition, cholesterol is abundant in the brain, especially in synapses and myelin membranes, and defective changes in cholesterol metabolism in peripheral organs and brain may promote or counteract the development of neurodegenerative diseases during aging, such as Alzheimer's disease, Huntington's disease, and Parkinson's disease[21]. In Alzheimer's disease, impaired cholesterol catabolism may lead to decreased biosynthesis of new cholesterol, and at the same time, the gradual accumulation of oxysterol, one of the products of cholesterol oxidation, which is involved in regulating neuronal dysfunction and degeneration, amyloid Aβ accumulation, and cell death[22,23]. However, the conversion of cholesterol to 24-hydroxycholesterol by CYP46A1 can regulate Sirtuin1 and prevent the neurotoxic accumulation of hyperphosphorylated tau protein, thus combating neurodegeneration[24]. In addition, cholesterol metabolism is closely related to the occurrence and development of osteoarthritis (OA). Cholesterol homeostasis plays an important role in bone development. Dysregulation of cholesterol metabolism is associated with abnormal lipid accumulation in chondrocytes, leading to OA. Statins may have chondroprotective and anti-inflammatory effects in OA progression[25].

CHANGES IN DIET MAY REDUCE HEPATOLITHIASIS

Dietary intake of high cholesterol foods and high intestinal cholesterol absorption are two important independent risk factors for the formation of cholesterol stones. Dietary habits control energy intake and play an important role in the occurrence and further development of metabolic disorders. A diet of refined sugars, high calories, high fat, low fiber and low protein increases the likelihood of intrahepatic bile duct stones[26]. High energy intake and increased BMI are risk factors for cholesterol stones. Research indicates that for every unit increase in BMI, the rate of symptomatic gallstones in women rises by 7% to 8%[27,28]. This may be because higher energy intake and increased BMI lead to increased triglycerides and decreased high density lipoprotein, leading to the secretion of gallbladder mucin[29]. One study tested a causal relationship between a variety of foods and cholelithiasis using Mendelian randomized trials. It was found that excessive intake of mutton and poultry increased the risk of cholelithiasis. In contrast, greater consumption of cooked vegetables, dried fruits and oily fish reduced the risk of cholelithiasis[30]. In addition, low fiber and vitamin C intake may increase cholesterol accumulation by decreasing colon motility and the efficiency of the liver's conversion of 7α-hydroxylated biliary cholesterol into bile acids[31,32]. Of course, foods also contain protective factors that prevent the formation of cholesterol stones. Firstly, eating many meals and avoiding eating on an empty stomach for a long period will promote the emptying of the gallbladder and prevent bile buildup. Secondly, olive oil, vegetable protein, fruits and other foods play a protective role and improve the risk of intrahepatic bile duct stone formation[33,34]. Certain special foods can influence the presence of intrahepatic bile duct stones. Research indicates that consuming moderate quantities of nuts on a weekly basis may lower the likelihood of requiring gallbladder removal, while drinking moderate amounts of alcohol can inhibit the conversion of high-density lipoprotein cholesterol mediated by cholesteryl ester transfer protein. Additionally, these foods may help protect against the formation of cholesterol stones[35].

In summary, intake of a low-calorie diet including fiber, vegetable protein, nuts, calcium, vitamin C, coffee and moderate alcohol together with physical exercise can effectively prevent the formation of hepatolithiasis.

TARGETED MEDICATION IS USED TO PREVENT HEPATOLITHIASIS

In the treatment of intrahepatic bile duct stones, the solubility of cholesterol in hepatic bile should be considered in addition to the formation and precipitation of bilirubin. As explained by Motta et al[1], ursodeoxycholic acid has been widely used in the dissolving treatment of cholesterol stones. On the one hand, ursodeoxycholic acid can significantly reduce various proteins and nuclear promoting activities in bile during treatment; on the other hand, it can also exert cholestrogenic activity and reduce the risk of recurrence after surgical or endoscopic lithotomy by stimulating liver and bile secretion function[5]. Research has indicated that patients with intrahepatic bile duct stones often have elevated levels of thiomucins and salivary mucins in their bile. These mucins can lower the pH of the bile, reducing the solubility of unbound bilirubin[36]. Selective COX-2 inhibitors and prostaglandin E (PGE) receptor antagonists appear to be excellent candidates. Increased COX-2-derived PGE2 synthesis in the bile duct and its mediated action through subtypes of prostaglandin E receptor (EP) may accelerate hepatolithiasis progression in patients. In in vitro studies, treatment with selective antagonists of EP subtype EP4 reduced the effect of PGE2 on DNA synthesis and myxoprotein secretion in bile duct epithelial cells[37]. Both fibrates and statins are excellent lipid-lowering drugs, and fibrates can slightly increase multidrug resistance protein 3 gene expression. Multidrug resistance protein 3 is the ATP binding cassette subfamily B member 4 (ABCB4) gene on chromosome 7 and encodes the ABCB4 protein. Treatment with the second-generation bate analogue benzabate can improve serum biliary enzyme levels in patients with primary biliary cirrhosis and has certain potential in the treatment of hepatolithiasis[38,39]. Statins are HMG-CoA reductase inhibitors, which have an inhibitory effect on liver cholesterol biosynthesis. Their discovery and application have led to rapid and sustained decreases in cholesterol levels when used alone. The high absorption rate of intestinal cholesterol is a risk factor for the development of gallstones. In the intestine, NPC1L1 plays an important role in providing diet to the body and reabsorbing cholesterol in bile. Ezetimibe is a highly selective inhibitor of intestinal cholesterol absorption. Inhibition of dietary and biliary cholesterol absorption across the intestinal cell brush border membrane through the NPC1L1 pathway significantly reduces biliary cholesterol saturation and delays cholesterol crystallization in the bile of patients with gallstones[40,41]. Inchin-ko-to is an herbal medicine and has long been considered a gallbladder relief and liver protection agent for various types of liver disease. Impaired expression and function of MRP2 (multidrug-resistant 2P-glycoprotein) in cholestasis may be an important target for specific pharmacological interventions. Inchin-ko-to is an effective drug used to stimulate and repair MRP2 expression and functional defects in hepatobiliary diseases such as hepatolithiasis[15,20]. During the process of cholesterol formation, the intestinal flora was seriously disordered and the abundance of beneficial bacteria significantly decreased, especially Lactobacillus and Akkermansia. is mostly used to treat a variety of metabolic gastrointestinal diseases and liver and bile diseases. Recently, studies have shown that Bupleurum shugan prevents the formation of cholesterol stones by restoring intestinal flora composition and reversing metabolic disorders in animal experiments[42]. The clinical application of this agent needs further confirmation.

CONCLUSION

Regular eating habits, reducing cholesterol intake and moderate physical exercise are effective ways to prevent intrahepatic bile duct stones. In addition, surgery is the first treatment choice in hepatolithiasis,. In the future, the use of targeted drugs at the same time as surgery, may be beneficial in treating hepatolithiasis.

ACKNOWLEDGEMENTS

We thank all subjects who participated in the manuscript.