Uridine diphosphate glucuronosyltransferase 1A1 prevents the progression of liver injury

BACKGROUND Uridine diphosphate glucuronosyltransferase 1A1(UGT1A1)plays a crucial role in metabolizing and detoxifying endogenous and exogenous substances.However,its contribution to the progression of liver damage remains unclear.AIM To determine the role and mechanism of UGT1A1 in liver damage progression.METHODS We investigated the relationship between UGT1A1 expression and liver injury through clinical research.Additionally,the impact and mechanism of UGT1A1 on the progression of liver injury was analyzed through a mouse model study.RESULTS Patients with UGT1A1 gene mutations showed varying degrees of liver damage,while patients with acute-onchronic liver failure(ACLF)exhibited relatively reduced levels of UGT1A1 protein in the liver as compared to patients with chronic hepatitis.This suggests that low UGT1A1 levels may be associated with the progression of liver damage.In mouse models of liver injury induced by carbon tetrachloride(CCl_(4))and concanavalin A(ConA),the hepatic levels of UGT1A1 protein were found to be increased.In mice with lipopolysaccharide or liver steatosis-mediated liver-injury progression,the hepatic protein levels of UGT1A1 were decreased,which is consistent with the observations in patients with ACLF.UGT1A1 knockout exacerbated CCl_(4)-and ConA-induced liver injury,hepatocyte apoptosis and necroptosis in mice,intensified hepatocyte endoplasmic reticulum(ER)stress and oxidative stress,and disrupted lipid metabolism.CONCLUSION UGT1A1 is upregulated as a compensatory response during liver injury,and interference with this upregulation process may worsen liver injury.UGT1A1 reduces ER stress,oxidative stress,and lipid metabolism disorder,thereby mitigating hepatocyte apoptosis and necroptosis.

Postoperative jaundice related to UGT1A1 and ABCB11 gene mutations:A case report and literature review

BACKGROUND Patients with obstructive jaundice caused by intrahepatic bile duct stones can be effectively managed by surgery.However,some patients may develop postope-rative complications,liver failure,and other life-threatening situations.Here,we report a patient with mutations in the uridine 5’-diphospho-glucuronosyltrans-ferase 1A1(UGT1A1)and bile salt export pump(adenosine triphosphate-binding cassette subfamily B member 11,ABCB11)genes who presented multiple intrahe-patic bile duct stones and cholestasis,and the jaundice of the patient increased after partial hepatectomy.CASE SUMMARY A 52-year-old male patient admitted to the hospital on October 23,2021,with a progressive exacerbation of jaundice,was found to have multiple intrahepatic bile duct stones with the diagnoses of obstructive jaundice and acute cholecystitis.Subsequently,the patient underwent left hepatectomy with biliary exploration,stone extraction,T-tube drainage,and cholecystectomy without developing any intraoperative complications.The patient had a dark urine color with worsening jaundice postoperatively and did not respond well to plasma exchange and other symptomatic and supportive treatments.Since the progressive increase in postoperative bilirubin could not be clinically explained with any potential reason,including,if not at all,viral infection,cholangitis,autoimmune liver disease,and other causes,the patient underwent whole-exon screening for any genetic diseases,which surprisingly identified UGT1A1 and ABCB11 gene mutations related to glucuronidation of indirect bilirubin as well as bile acid transport in hepatocytes,respectively.Thus,we hypothesized that postoperative refractory cholestasis might result from UGT1A1 and ABCB11 gene mutations and further recommended liver transplantation to the patient,who eventually declined it and died from liver failure six months later.CONCLUSION Surgery may aggravate cholestasis in patients with multiple intrahepatic bile duct stones and cholestasis associated with UGT1A1 and ABCB11 gene mutations.A liver transplant may be the best option if active medical treatment fails.

Relationship of familial cytochrome P450 4V2 gene mutation with liver cirrhosis:A case report and review of the literature

BACKGROUND Many genetic and metabolic diseases affect the liver,but diagnosis can be difficult because these diseases may have complex clinical manifestations and diverse clinical patterns.There is also incomplete clinical knowledge of these many different diseases and limitations of current testing methods.CASE SUMMARY We report a 53-year-old female from a rural area in China who was hospitalized for lower limb edema,abdominal distension,cirrhosis,and hypothyroidism.We excluded the common causes of liver disease(drinking alcohol,using traditional Chinese medicines,hepatitis virus infection,autoimmunity,and hepatolenticular degeneration).When she was 23-years-old,she developed night-blindness that worsened to complete blindness,with no obvious cause.Her parents were first cousins,and both were alive.Analysis of the patient’s family history indicated that all 5 siblings had night blindness and impaired vision;one sister was completely blind;and another sister had night-blindness complicated with cirrhosis and subclinical hypothyroidism.Entire exome sequencing showed that the patient,parents,and siblings all had mutations in the cytochrome P450 4V2gene(CYP4V2).The CYP4V2 mutations of the parents and two sisters were heterozygous,and the others were homozygous.Two siblings also had heterozygous dual oxidase activator 2(DUOXA2) mutations.CONCLUSION Mutations in the CYP4V2 gene may affect lipid metabolism and lead to chronic liver injury,fibrosis,and cirrhosis.