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Serum glutamate dehydrogenase activity enables early detection of liver injury in subjects with underlying muscle impairments.

ABSTRACT: Serum activities of alanine and aspartate aminotransferases (ALT and AST) are used as gold standard biomarkers for the diagnosis of hepatocellular injury. Since ALT and AST lack liver specificity, the diagnosis of the onset of hepatocellular injury in patients with underlying muscle impairments is severely limited. Thus, we evaluated the potential of glutamate dehydrogenase (GLDH) as a liver specific alternative biomarker of hepatocellular injury. In our study, serum GLDH in subjects with Duchene muscular dystrophy (DMD) was equivalent to serum GLDH in age matched healthy subjects, while serum ALT was increased 20-fold in DMD subjects. Furthermore, serum GLDH in 131 subjects with variety of muscle impairments was similar to serum GLDH of healthy subjects while serum ALT corelated with serum creatine kinase, a widely accepted biomarker of muscle impairment. In addition, significant elevations of ALT, AST, and CK were observed in a case of a patient with rhabdomyolysis, while serum GLDH stayed within the normal range until the onset of hypoxia-induced liver injury. In a mouse model of DMD (DMDmdx), serum GLDH but not serum ALT clearly correlated with the degree of acetaminophen-induced liver injury. Taken together, our data support the utility of serum GLDH as a liver-specific biomarker of liver injury that has a potential to improve diagnosis of hepatocellular injury in patients with underlying muscle impairments. In drug development, GLDH may have utility as a biomarker of drug induced liver injury in clinical trials of new therapies to treat muscle diseases such as DMD.

SUBMITTER: Schomaker S

PROVIDER: S-EPMC7224523 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Serum glutamate dehydrogenase activity enables early detection of liver injury in subjects with underlying muscle impairments.

Schomaker Shelli S Potter David D Warner Roscoe R Larkindale Jane J King Nicholas N Porter Amy C AC Owens Jane J Tomlinson Lindsay L Sauer John-Michael JM Johnson Kent K Aubrecht Jiri J

PloS one 20200514 5

Serum activities of alanine and aspartate aminotransferases (ALT and AST) are used as gold standard biomarkers for the diagnosis of hepatocellular injury. Since ALT and AST lack liver specificity, the diagnosis of the onset of hepatocellular injury in patients with underlying muscle impairments is severely limited. Thus, we evaluated the potential of glutamate dehydrogenase (GLDH) as a liver specific alternative biomarker of hepatocellular injury. In our study, serum GLDH in subjects with Duchen ...[more]

PMID: 32407333

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Project description:Glutamate dehydrogenase is an important enzyme in the hepatic regulation of nitrogen and energy metabolism. It catalyzes one of the most relevant anaplerotic reactions. Although its relevance in liver homeostasis has been widely described, its daily pattern and responsiveness to restricted feeding protocols has not been studied. We explored the daily variations of liver glutamate dehydrogenase transcription, protein, activity, and histochemical and subcellular location in a protocol of daytime food synchronization in rats. Restricted feeding involved food access for 2 h each day for three weeks. Control groups included food ad libitum as well as acute fasting (21 h fasting) and refeeding (22 h fasting followed by 2 h of food access). Glutamate dehydrogenase mRNA, protein, activity, and histological location were measured every 3 h by qPCR, Western blot, spectrophotometry, and immunohistochemistry, respectively, to generate 24-h profiles. Restricted feeding promoted higher levels of mitochondrial glutamate dehydrogenase protein and activity, as well as a loss of 24-h rhythmicity, in comparison to ad libitum conditions. The rhythmicity of glutamate dehydrogenase activity detected in serum was changed. The data demonstrated that daytime restricted feeding enhanced glutamate dehydrogenase protein and activity levels in liver mitochondria, changed the rhythmicity of its mRNA and serum activity, but without effect in its expression in hepatocytes surrounding central and portal veins. These results could be related to the adaptation in nitrogen and energy metabolism that occurs in the liver during restricted feeding and the concomitant expression of the food entrainable oscillator. Impact statement For the first time, we are reporting the changes in daily rhythmicity of glutamate dehydrogenase (GDH) mRNA, protein and activity that occur in the liver during the expression of the food entrained oscillator (FEO). These results are part of the metabolic adaptations that modulate the hepatic timing system when the protocol of daytime restricted feeding is applied. As highlight, it was demonstrated higher GDH protein and activity in the mitochondrial fraction. These results contribute to a better understanding of the influence of the FEO in the energy and nitrogen handling in the liver. They could also be significant in the pathophysiology of hepatic diseases related with circadian abnormalities.

Dataset Information

Serum glutamate dehydrogenase activity enables early detection of liver injury in subjects with underlying muscle impairments.

Publications

Serum glutamate dehydrogenase activity enables early detection of liver injury in subjects with underlying muscle impairments.

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