Targeting uridine diphosphate glucuronosyltransferase 1A1 in liver disease: Current research and future directions

Abstract

The current letter to the editor pertains to the manuscript entitled 'Uridine diphosphate glucuronosyltransferase 1A1 prevents the progression of liver injury'. Increased levels of uridine diphosphate glucuronosyltransferase 1A1 during liver injury could mitigate damage by reducing endoplasmic reticulum stress, oxidative stress, and dysregulated lipid metabolism, impeding hepatocyte apoptosis and necroptosis.

Key Words: Uridine diphosphate glucuronosyltransferase 1A1; Liver injury; Endoplasmic reticulum stress; Oxidative stress; Lipid metabolism disorders

Core Tip: During liver injury, expression of the uridine diphosphate glucuronosyltransferase (UGT) 1A1 enzyme increases. Interfering with this increase in expression can potentially worsen liver damage. The beneficial effects of UGT1A1 in reducing liver injury might stem from its capacity to alleviate hepatocyte apoptosis and necroptosis, which are driven by endoplasmic reticulum stress, oxidative stress, and abnormal lipid metabolism.

TO THE EDITOR

We read with great interest the recent study by Jiang et al[1], which reported that uridine diphosphate glucuronosyltransferase (UGT) 1A1 ameliorates the severity of liver damage in various mouse injury models. Prolonged and unmanaged acute liver injury (ALI) can progress to liver fibrosis or more advanced cirrhosis, which is irreversible. Additionally, there are no drugs approved by the Food and Drug Administration to treat liver fibrosis. Hence, treatment of ALI plays an essential role in preventing disease progression in the liver.

UGT1A1, located at the endoplasmic reticulum of hepatocytes, is a phase II metabolic enzyme that catalyzes the glucuronidation reaction. This reaction involves adding a glucuronic acid moiety to substrates, making them more water-soluble and facilitating their elimination from the body[2,3]. UGT1A1 plays a crucial role in the metabolism and excretion of bilirubin, an endogenous compound produced from the breakdown of heme. UGT1A1 also metabolizes and detoxifies various drugs, environmental toxins, and other xenobiotic compounds[4]. Therefore, mutations in UGT1A1 are implicated in various fatal clinical outcomes due to hyperbilirubinemia[5-7].

Interestingly, this study found mutations in the UGT1A1 gene to be associated with liver diseases and the significantly lower expression of UGT1A1 in patients with acute-on-chronic liver failure compared to those with chronic hepatitis. Moreover, patients with a UGT1A1 mutation in this study showed increased unconjugated bilirubin (indirect bilirubin), consistent with characteristics of patients with genetic diseases involving UGT1A1[8]. Similarly, a decline in Ugt1a1 level was observed in mice with more severe ALI induced by carbon tetrachloride (CCl₄) plus lipopolysaccharide or a high-fat diet treatment compared to mice with ALI induced by CCl₄ alone. Recent research also showed that Ugt1a1 expression was decreased in mice with schistosomiasis-induced liver fibrosis[9]. These observations imply protective effects of UGT1A1 related to bilirubin metabolism in the context of liver injury. Indeed, the depletion of Ugt1a1 in mice demonstrated more severe liver injury upon CCl₄ and concanavalin A treatment. The authors further decipher the molecular mechanism by which UGT1A1 affects the progression of liver injury in mice. Intriguingly, reduced activity and low levels of UGT1A1 exacerbated endoplasmic reticulum (ER) stress, oxidative stress, and disruptions in lipid metabolism. This aggravation resulted in increased hepatocyte apoptosis and necroptosis, crucial types of programmed cell death[10], promoting the progression of liver injury.

Since complete loss of UGT1A1 function is fatal, Ugt1a1 knockout mice survive for only around 20 days[1]. Therefore, heterozygous Ugt1a1^+/− mice were employed in a previous study, indicating that the livers of Ugt1a1^+/- mice had more severe injury and accumulated higher levels of unconjugated bilirubin after the injection of bilirubin[11]. Moreover, humanized UGT1 (hUGT1) mice, which carry the nine human UGT1A genes linked to the UGT1 locus on a Ugt1-null background, displayed hyperbilirubinemia that was alleviated after the induction of UGT1A1[12]. These findings are further supported by the current study, which shows the sensitization of liver injury by Ugt1a1 knockdown in mice. Thus, this study extends our knowledge about the role of UGT1A1 in ALI, specifically in ER stress, oxidative stress, and lipid metabolism[1].

However, the limitation of this study is the absence of specific information on expression of Cas9 within the liver or whether the AAV8 vector contains the liver-specific thyroid hormone-binding globulin promoter to express Ugt1a1 single-guide RNA in hepatocytes. Moreover, since the Ugt1a1 gene was not fully knocked down in this study, it would be valuable to conduct additional studies using hepatocyte-specific Ugt1a1 knockout mice through tamoxifen-inducible Cre-loxP systems or AAV8-TBG-Cre injections[13,14].

The future of UGT1A1 research looks promising, with potential developments in gene therapy and more precise pharmacological targeting. More comprehensive studies to understand the interaction of UGT1A1 with various signaling pathways in liver disease are needed. Additionally, exploration of the exact role of this enzyme in other diseases offers an interdisciplinary approach to its use.

In conclusion, these findings indicate a pivotal role of UGT1A1 in the pathogenesis of ALI. Its comprehensive understanding will undoubtedly enhance the development of diagnostic tools and therapeutic regimens to overcome acute or chronic liver injury. Hence, we should pay close attention to UGT1A1.