Biomarkers for liver disease in urea cycle disorders

Nagamani, Sandesh C.S.; Ali, Saima; Izem, Rima; Schady, Deborah; Masand, Prakash; Shneider, Benjamin L.; Leung, Daniel H.; Burrage, Lindsay C.

doi:10.1016/j.ymgme.2021.04.001

Cited by 11 publications

(12 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Most notably, the expression of proteins involved in nitrogen processing is induced, causing an increase in ammonia and urea levels in the liver and blood [ 40 , 43 ]. In several different studies, aberrations in the urea cycle were connected with higher rates of liver inflammation, increased liver disease burden, and liver pathologies [ 44 , 45 , 46 , 47 ]. This mechanism could explain the observed increase in inflammation upon the start of a high-protein diet via the activation of innate immune cells.…”

Section: Discussionmentioning

confidence: 99%

Activation of Granulocytes in Response to a High Protein Diet Leads to the Formation of Necrotic Lesions in the Liver

et al. 2023

View full text Add to dashboard Cite

In their aspiration to become healthy, people are known to follow extreme diets. However, the acute impact on organs regulating systemic metabolism is not well characterized. Here, we investigated the acute impact of six extreme diets on the liver in mice. Most diets did not lead to clear pathology after short-term feeding. However, two weeks of feeding with a high protein diet (HPD) resulted in an acute increase of liver enzymes in the blood, indicative of liver damage. Histology revealed the formation of necrotic lesions in this organ which persisted for several weeks. Flow cytometric analysis of hepatic immune cell populations showed that HPD feeding induced activation of macrophages and neutrophils. Neutralization of the pro-inflammatory cytokine IL-1β or depletion of macrophages with clodronate-loaded liposomes or with genetic models did not ameliorate liver necrosis. In contrast, the depletion of neutrophils prevented HPD-induced hepatic inflammation. After prolonged feeding, HPD-feeding was associated with a strong increase of the cytokines IL-10 and IL-27, suggesting that anti-inflammatory mediators are activated to prevent nutrient-overload-induced damage to the liver. In summary, whereas our data indicates that most extreme diets do not have a major impact on the liver within two weeks, diets with a very high protein content may lead to severe, acute hepatic damage and should therefore be avoided.

show abstract

Section: Discussionmentioning

confidence: 99%

Activation of Granulocytes in Response to a High Protein Diet Leads to the Formation of Necrotic Lesions in the Liver

et al. 2023

View full text Add to dashboard Cite

show abstract

“…The liver pathology persists and can worsen despite appropriate ammonia control under standard of care, suggesting hyperammonaemia is not the sole cause (7). Accumulation of toxic metabolites such as argininosuccinic acid, potentially facilitated by high arginine supplementation could be contributing factors (6, 9, 34).…”

Section: Discussionmentioning

confidence: 99%

“…Early-onset patients display hyperammonemia, while late-onset patients present with either acute hyperammonaemia and/or chronic phenotype of neurocognitive impairment and liver disease (3). Compared to other UCDs, ASA is associated with a high burden of chronic liver complications such as elevated levels of serum transaminases, hepatomegaly, fibrosis, steatosis, hepatocellular injury and glycogen storage both in patients (6)(7)(8)(9)(10) and in the mouse model Asl Neo/Neo (8,11). Some patients present with liver cirrhosis or, rarely, hepatocellular carcinoma (9,12,13).…”

Section: Introductionmentioning

confidence: 99%

“…Some patients present with liver cirrhosis or, rarely, hepatocellular carcinoma (9, 12, 13). The underlying processes that trigger liver disease are unclear, but suggested mechanisms include hyperammonaemia, arginine deficiency, argininosuccinate toxicity, NO deficiency and oxidative stress (6, 9). More detailed mechanistic insight into liver pathophysiology will be crucial to identifying optimal diagnostic markers for better assessment of disease severity, prediction of disease progression and assessment of response to therapy.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

mRNA therapy restores ureagenesis and corrects glutathione metabolism in argininosuccinic aciduria

Gurung

Timmermand

Perocheau

et al. 2022

Preprint

View full text Add to dashboard Cite

Argininosuccinate lyase (ASL) is a key enzyme integral to the hepatic urea cycle which is required for ammonia detoxification, and the citrulline-nitric oxide (NO) cycle for NO production. ASL deficient patients present with argininosuccinic aciduria (ASA), an inherited metabolic disease with hyperammonaemia and a chronic systemic phenotype with neurocognitive impairment and chronic liver disease. ASL deficiency as an inherited model of systemic NO deficiency, shows enhanced nitrosative and oxidative stress. Here, we describe the dysregulation of glutathione biosynthesis and upstream cysteine utilization in ASL-deficient patients and mice using targeted metabolomics andin vivopositron emission tomography (PET) imaging using (S)-4-(3-18F-fluoropropyl)-L-glutamate ([18F]FSPG). Upregulation of cysteine metabolism contrasted with glutathione depletion and down-regulated antioxidant pathways.hASLmRNA encapsulated in lipid nanoparticles corrected and rescued the neonatal and adult Asl-deficient mouse phenotypes, respectively, enhancing ureagenesis and glutathione metabolism and ameliorating chronic liver disease. We further present [18F]FSPG PET as a novel non-invasive diagnostic tool to assess liver disease and therapeutic efficacy in ASA. These findings support clinical translation of mRNA therapy for ASA.

show abstract

“…Chronic liver dysfunction causes morbidity in all UCD subtypes (13,14) but is reported with higher frequency and severity in ASA (1,11,13,15). This liver disease commonly manifests with hepatomegaly and transaminitis and can progress to liver failure and, eventually, hepatocellular carcinoma (11,(14)(15)(16)(17)(18)(19). Liver pathology progresses despite appropriate ammonia control, suggesting that hyperammonemia is not the sole cause (14).…”

Section: Introductionmentioning

confidence: 99%

mRNA therapy corrects defective glutathione metabolism and restores ureagenesis in preclinical argininosuccinic aciduria

Gurung,

Timmermand,

Perocheau

et al. 2024

Sci. Transl. Med.

View full text Add to dashboard Cite

The urea cycle enzyme argininosuccinate lyase (ASL) enables the clearance of neurotoxic ammonia and the biosynthesis of arginine. Patients with ASL deficiency present with argininosuccinic aciduria, an inherited metabolic disease with hyperammonemia and a systemic phenotype coinciding with neurocognitive impairment and chronic liver disease. Here, we describe the dysregulation of glutathione biosynthesis and upstream cysteine utilization in ASL-deficient patients and mice using targeted metabolomics and in vivo positron emission tomography (PET) imaging using ( S )-4-(3- 18 F-fluoropropyl)- l -glutamate ([ 18 F]FSPG). Up-regulation of cysteine metabolism contrasted with glutathione depletion and down-regulated antioxidant pathways. To assess hepatic glutathione dysregulation and liver disease, we present [ 18 F]FSPG PET as a noninvasive diagnostic tool to monitor therapeutic response in argininosuccinic aciduria. Human hASL mRNA encapsulated in lipid nanoparticles improved glutathione metabolism and chronic liver disease. In addition, hASL mRNA therapy corrected and rescued the neonatal and adult Asl-deficient mouse phenotypes, respectively, enhancing ureagenesis. These findings provide mechanistic insights in liver glutathione metabolism and support clinical translation of mRNA therapy for argininosuccinic aciduria.

show abstract

Biomarkers for liver disease in urea cycle disorders

Cited by 11 publications

References 46 publications

Activation of Granulocytes in Response to a High Protein Diet Leads to the Formation of Necrotic Lesions in the Liver

Activation of Granulocytes in Response to a High Protein Diet Leads to the Formation of Necrotic Lesions in the Liver

mRNA therapy restores ureagenesis and corrects glutathione metabolism in argininosuccinic aciduria

mRNA therapy corrects defective glutathione metabolism and restores ureagenesis in preclinical argininosuccinic aciduria

Contact Info

Product

Resources

About