Jia Fan
Dongxu Wang- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, China
Nonalcoholic fatty liver disease (NAFLD) is characterized by over 5% hepatic fat accumulation without secondary causes. The prevalence of NAFLD has escalated in recent years due to shifts in dietary patterns and socioeconomic status, making it the most prevalent chronic liver disease and a significant public health concern globally. Serum uric acid (SUA) serves as the end product of purine metabolism in the body and is intricately linked to metabolic syndrome. Elevated SUA levels have been identified as an independent risk factor for the incidence and progression of NAFLD. This paper reviews the relationship between SUA and NAFLD, the underlying mechanisms of SUA involved in NAFLD, and the potential benefits of SUA-lowering therapy in treating NAFLD. The aim is to raise awareness of SUA management in patients with NAFLD, and to encourage further investigation into pharmacological interventions in this area.
1 Introduction
Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological condition characterized by over-accumulation of fat in the liver, defined as steatosis in over 5% of hepatocytes, in the absence of alcohol consumption and other definitive factors causing liver damage (1, 2). The prevalence of NAFLD has been steadily rising due to changes in lifestyle and dietary patterns, making it the most common chronic liver ailment globally (3, 4). The global prevalence of NAFLD is 30.1% (5), with Asian countries reporting a prevalence of 29.6% (6). NAFLD not only has the potential to progress to cirrhosis and liver cancer but is also linked to cardiovascular and cerebrovascular diseases, peripheral vascular diseases, diabetes mellitus, cholelithiasis, and other conditions, as well as an increased risk of various malignant tumors such as colorectal, breast, and pancreatic cancers (7–9). NAFLD is a serious threat to the health of human beings, and it has become a major global concern (10, 11). Given the widespread use of the term NAFLD in existing literature, despite recent proposals to rename it as metabolic-associated fatty liver disease (MAFLD) (12), this review will continue to refer to it as NAFLD.
Uric acid (UA) is the final product of purine compound breakdown in the liver (13), with xanthine oxidase (XO) playing a crucial role in its production by catalyzing the oxidation from hypoxanthine to xanthine and then to UA (14). Abnormalities in UA metabolism are associated with several chronic systemic diseases like hypertension, atherosclerosis, diabetes mellitus, and dyslipidemia (15–17). The relationship between serum uric acid (SUA) levels and NAFLD severity has gained attention in recent years, with SUA being a significant factor independently correlated with the severity of NAFLD independently of other metabolic markers (18). Studies have reported a 21% increase in NAFLD risk for every 1 mg/dL rise in SUA levels (19), with hyperuricemia further elevating the risk of significant liver fibrosis in NAFLD patients (20).
In order to gain a deeper comprehension of the correlation between SUA and NAFLD, this review aims to synthesize current research findings to aid in the management of SUA levels in NAFLD patients.
2 Relationship between SUA and NAFLD
A Meta-analysis has shown a pooled odds ratio of 1.88 in NAFLD patients with higher SUA levels compared to those with lower levels, with SUA levels being associated with NAFLD across various subgroups regardless of study quality, study design, sample size, age, gender, or country (21). Elevated SUA levels are also linked to the severity and progression of NAFLD, with studies indicating a strong correlation between SUA levels and the degree of steatosis, inflammation of the lobules, cirrhosis development, and elevated liver enzymes in NAFLD patients (22, 23). While obesity is a known risk factor for NAFLD (24), increased SUA levels in non-obese individuals significantly heighten the risk of NAFLD, surpassing that in obese patients with normal SUA levels (25). Table 1 provides an overview of relevant studies on the relationship between SUA on NAFLD (18, 22, 25–61).
Table 1. Studies on the relationship between SUA on NAFLD.
3 Underlying mechanisms of SUA involved in NAFLD
The pathogenesis of NAFLD has transitioned from the “two-hit” theory to the “multiple hit” hypothesis, which suggests that various factors collectively contribute to the development of NAFLD in genetically susceptible individuals (63, 64). These factors include steatosis, inflammation, oxidative stress (OS), metabolic dysfunction, and insulin resistance (IR) (63, 64). The precise mechanisms through which SUA is involved in NAFLD remain incompletely understood. SUA plays a role in the onset and progression of NAFLD through processes such as OS, inflammatory responses, disturbances in lipid metabolism, and IR, as shown in Figure 1.
Figure 1. Underlying mechanisms of SUA involved in NAFLD. NAFLD, nonalcoholic fatty liver disease; SUA, serum uric acid; ROS, reactive oxygen species; UA, uric acid; NADPH, nicotinamide adenine dinucleotide phosphate; XO, xanthine oxidase; NF-κB, nuclear factor kappa-B; NLRP3, nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3; SREBP1, sterol regulatory element binding protein 1; FASN, fatty acid synthase; LDL-C, low-density lipoprotein cholesterol; TG, liver fat content; JNK, c-Jun N-terminal kinase; AP-1, activator protein-1; FGF21, fibroblast growth factors 21; IRS1, insulin receptor substrate 1; Akt, protein kinase B; eNOS, endothelial nitric oxide synthase. Red arrows, up-regulation of expression or enhanced activity. Green arrows, down-regulation of expression or reduced activity.
3.1 Oxidative stress
OS is an important etiopathogenesis of NAFLD (65). Elevated levels of reactive oxygen species (ROS) under OS can lead to dysfunction in mitochondria and endoplasmic reticulum, as well as reduced antioxidant defenses in liver cells, resulting in inflammation, cell death, and fibrosis during NAFLD progression (66). Hepatocytes exposed to UA has been linked to mitochondrial OS mediated by the translocation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (67). UA also enhances fat synthesis in hepatocytes by facilitating the transfer of NADPH oxidase subunit 4 to mitochondria, thereby increasing superoxide production (68). Xanthine oxidase (XO), the rate-limiting enzyme enzyme for UA production, generates ROS during catalyzing the oxidative hydroxylation of hypoxanthine and xanthine to produce UA (69). SUA levels can serve as an indicator of XO activity in NAFLD (70). In addition, 70% of fructose in the human body is metabolized by the liver, and fructose-rich diets can exacerbate NAFLD (71). Fructose can exacerbate NAFLD by promoting hepatic fat accumulation through both direct triglyceride (TG) synthesis from fructose metabolism and an uric acid-dependent pathway via mitochondrial OS (72).
3.2 Inflammatory responses
Inflammation is a fundamental component of NAFLD pathophysiology and is present throughout the disease progression (73). UA is a potent inflammatory inducer, capable of upregulating the expression of various inflammation markers in a dose-dependent manner (74). It may also trigger the activation of pro-inflammatory signaling pathways, such as nuclear factor kappa-B, leading to the expression of inflammatory molecules and exacerbating the inflammatory response in hepatocytes (74). The nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, a multiprotein complex involved in recognizing pathogens and molecular patterns, plays a crucial role in obesity, IR, and NAFLD progression (75–77). UA, as an injury-related molecular pattern, stimulates macrophage recruitment (78, 79), which then expresses NLRP3 inflammasome and generate significant quantities of IL-1β (80, 81), leading to chronic inflammation in hepatocytes. UA also exacerbate hepatic inflammation by inducing immune responses through dendritic cells (82).
3.3 Lipid metabolism
The onset of NAFLD is linked to disruptions in lipid metabolism (83). UA plays a role in regulating fatty acid synthase (FASN) through the sterol regulatory element binding protein 1 (SREBP1) signaling pathway, resulting in the accumulation of free fatty acids and compromised energy metabolism in HepG2 cells (84). Additionally, UA triggers the activation of SREBP-1c via endoplasmic reticulum stress, promoting lipid synthesis in hepatocytes, which in turn exacerbates intracellular fat accumulation and lipid degeneration in hepatocytes (85). UA exacerbates lipid metabolism disorders in NAFLD by oxidatively modifying low-density lipoprotein cholesterol and TG synthesis (86). Furthermore, UA facilitates the conversion of fructose to fructose 1-phosphate by activating fructokinase in hepatocytes, leading to fat accumulation through gluconeogenesis (87). Mitochondrial OS induced by UA inhibits aconitase in the Krebs cycle, causing citric acid buildup and stimulating enzymes involved in fatty acid synthesis, ultimately promoting de novo lipogenesis (72). UA significantly up-regulates the expression of miR-149-5p in hepatocytes, and FGF21, a downstream target of miR-149-5p and closely related to lipid metabolism, whose deficiency can lead to hepatic steatosis, so that uric acid aggravated hepatic fat accumulation through the miR-149-5p/FGF21 axis (67). UA upregulates the expression of lipogenic genes in hepatocytes via the ROS/JNK//AP-1 pathway, increasing triglyceride levels in HepG2 cells and leading to the accumulation of intracellular fat in hepatocytes (88).
3.4 Insulin resistance
NAFLD is closely linked to IR, with some considering NAFLD as a hepatic manifestation of IR (89, 90). Obesity is associated with the development of chronic low-grade inflammation, a condition exacerbated by the expansion of adipose tissue (91, 92). The inflammatory characteristics of adipose tissue enhance cytokine production, which in turn contributes to the development of IR (93, 94). In the state of IR, there is an upregulation of lipolysis in adipose tissue, resulting in an increased influx of free fatty acids to the liver (95). Concurrently, hyperinsulinemia stimulates lipogenesis in hepatocytes (96). These metabolic alterations culminate in lipid accumulation within the liver, leading to an increase in intracellular lipid peroxidation products and cytotoxic agents (97). Ultimately, these processes contribute to the onset and progression of NAFLD.The concentration of SUA was found to be independently related with IR (98). UA can inhibit insulin signaling pathways and induce IR by various mechanisms, including activation of the NLRP3 inflammasome and inhibition of IRS1/Akt pathway (72, 99). Elevated SUA levels cause the deposition of urate crystals in pancreatic islets, impairing pancreatic β-cell function and worsening IR (100). Reduced activity of endothelial nitric oxide synthase is also implicated in increased IR in individuals with hyperuricemia (17). Through the aforementioned mechanisms, UA intensifies the level of IR within the body and facilitates the advancement of NAFLD.
4 Potential benefits of SUA-lowering therapy in treating NAFLD
Despite the increasing global prevalence of NAFLD, there remain no FDA-approved pharmacological treatments specifically designed to address this condition, largely due to its intricate pathogenesis and multifactorial nature (101). Currently, lifestyle modifications, including substantial weight loss achieved through a low-calorie diet and increased physical activity, are regarded as the primary interventions for both the prevention and management of NAFLD, as weight reduction is correlated with a decrease in liver fat and may facilitate the reversal of disease progression (102). Bariatric surgery has the potential to decrease hepatic steatosis in obese patients with NAFLD (103). Nevertheless, it is important to note that NAFLD is not considered a valid indication for bariatric surgery (104). In terms of pharmacotherapy, the European and American Association for the Study of the Liver recommends the administration of vitamin E and pioglitazone exclusively for select patients diagnosed with NAFLD (105). More current research hotspots regarding therapeutic agents for NAFLD are mainly focused on drug selection against different metabolic targets (106). Given the significant relationship between SUA levels and NAFLD development, researchers have now recognized that SUA-lowering therapy may have a valuable contribution for improving NAFLD outcomes. XO inhibitors like febuxostat and allopurinol are commonly used to lower SUA levels and have shown promise in improving NAFLD in various studies.
Allopurinol, when administered at a daily dose of 100 mg to patients with hyperuricemia, has been found to lead to a significant reduction in the hepatic controlled attenuation parameter score after a three-month period (107). This medication has demonstrated the ability to decrease TG content in HepG2 cells and in the livers of NAFLD mice by inhibiting XO activity (108, 109). Moreover, allopurinol has shown efficacy in reducing histopathological scores and levels of interleukin-1 (IL-1) and IL-2 immunoexpression in the livers of NAFLD rats (110). By inhibiting NRLP3 inflammasome activation, allopurinol has been observed to mitigate hepatic steatosis and IR by lowering SUA levels (78). In diabetic rats, allopurinol has been found to improve hepatic OS and liver injury through the activation of the Nrf2/p62 pathway (111), as well as to reduce hepatic inflammation and lipid accumulation by decreasing hepatic thioredoxin levels (112). Additionally, allopurinol has been demonstrated to enhance fatty acid beta-oxidation in mouse livers and alleviate high fructose diet-induced hepatic steatosis in diabetic rats by modulating inflammation, lipid metabolism, and endoplasmic reticulum stress pathways (113, 114).
On the other hand, febuxostat has demonstrated a more favorable hepatic safety profile in gout patients with NAFLD (115). Treatment with febuxostat for 24 weeks has resulted in reduced SUA levels, as well as decreased levels of aspartate aminotransferase and alanine aminotransferase in NAFLD patients with hyperuricemia (116). In a nonalcoholic steatohepatitis (NASH) mouse model, febuxostat significantly lowered hepatic XO activity and UA levels, leading to improvements in IR, lipid peroxidation, and the accumulation of classically activated M1-like macrophages in the liver (116). Furthermore, febuxostat has been shown to reduce fat accumulation and ROS in HepG2 cells and NASH mice by downregulating the expression of NLRP3/caspase-1/IL-18/IL-1β and improving IR (117). Administration of febuxostat has also been found to normalize fatty acid oxidation-related genes, collagen deposition, fibrotic changes, lipid peroxidation, and inflammatory cytokine expressions in NASH mice (118).
While both XO inhibitors demonstrated comparable effects in lowering UA levels in the bloodstream, febuxostat exhibited a significant reduction in hepatic UA levels and XO activity in a NASH model in mice, a response not observed with allopurinol (116). This decrease in hepatic UA levels and XO activity was associated with a more pronounced prevention of specific NASH characteristics, including IR, lipid peroxidation, the aggregation of classically activated M1-like macrophages, and hepatic inflammation (116). These findings suggest that febuxostat may possess greater potential for ameliorating NAFLD in patients suffering from hyperuricemia.
5 Limitations
Currently, although advancements have been made in understanding the relationship between SUA levels and NAFLD and proposed a new direction and goal for solving the multifactorial problem of fatty liver, this area of research still faces several limitations. There is a pressing need for more fundamental experimental studies to elucidate the mechanisms through which SUA influences the development of NAFLD, particularly those mechanisms that are directly implicated in the pathogenesis of NAFLD, and the strengths and potential limitations of SUA and its direct association with OS. Observational studies investigating the effects of SUA-lowering therapies on NAFLD have primarily been conducted in preclinical settings or among specific populations with hyperuricemia. This is largely attributable to the insufficient recognition and valuation of SUA-lowering agents in clinical practice for the management of NAFLD, and SUA-lowering therapies on NAFLD is necessitated further investigation into their efficacy and safety, while also focusing on its effects on body weight, glucose and lipid metabolism, and liver tissue pathology. Furthermore, there is a notable absence of research conclusions regarding the use of SUA-lowering therapies for the prevention of NAFLD, as well as the impact of such treatments on NAFLD population without hyperuricemia. To address these gaps, more extensive, long-term, multi-center clinical studies are required to assess the potential benefits of these interventions.
6 Conclusion
In summary, there is a correlation between SUA and NAFLD, with SUA potentially exacerbating NAFLD through various pathways such as OS, inflammatory responses, lipid metabolism disturbances, and IR. Research has explored the potential benefits of SUA-lowering interventions in improving NAFLD. Given the global prevalence of NAFLD and the current limitations in treatment options, identifying novel therapeutic targets for NAFLD is imperative. Targeting XO inhibition as a SUA-lowering therapy may represent a promising avenue for future NAFLD management.
Author contributions
JF: Writing – original draft. DW: Writing – review & editing.
Funding
The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was funded by Liaoning Provincial Science and Technology Programme Joint Fund for Doctoral Research Initiation Project, grant number 2023-BSBA-349.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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Keywords: nonalcoholic fatty liver disease, serum uric acid, xanthine oxidase, oxidative stress, NLRP3 inflammasome, lipid metabolism, insulin resistance
Citation: Fan J and Wang D (2024) Serum uric acid and nonalcoholic fatty liver disease. Front. Endocrinol. 15:1455132. doi: 10.3389/fendo.2024.1455132
Received: 26 June 2024; Accepted: 11 November 2024;
Published: 28 November 2024.
Edited by:
Roger Gutiérrez-Juárez, National Autonomous University of Mexico, MexicoReviewed by:
Berwin Singh Swami Vetha, East Carolina University, United StatesJiachen Sun, Dana–Farber Cancer Institute, United States
Yongxiang Li, Baylor College of Medicine, United States
Copyright © 2024 Fan and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Dongxu Wang, ZG9uZ3h1d2FuZ2R4QDEyNi5jb20=