Flux analysis of inborn errors of metabolism

Abstract

Patients with an inborn error of metabolism (IEM) are deficient of an enzyme involved in metabolism, and as a consequence metabolism reprograms itself to reach a new steady state. This new steady state underlies the clinical phenotype associated with the deficiency. Hence, we need to know the flux of metabolites through the different metabolic pathways in this new steady state of the reprogrammed metabolism. Stable isotope technology is best suited to study this. In this review the progress made in characterizing the altered metabolism will be presented. Studies done in patients to estimate the residual flux through the metabolic pathway affected by enzyme deficiencies will be discussed. After this, studies done in model systems will be reviewed. The focus will be on glycogen storage disease type I, medium-chain acyl-CoA dehydrogenase deficiency, propionic and methylmalonic aciduria, urea cycle defects, phenylketonuria, and combined D,L-2-hydroxyglutaric aciduria. Finally, new developments are discussed, which allow the tracing of metabolic reprogramming in IEM on a genome-wide scale. In conclusion, the outlook for flux analysis of metabolic derangement in IEMs looks promising.

Intracellular lipids are an independent cause of liver injury and chronic kidney disease in non alcoholic fatty liver disease-like context

“…Indeed, the increased utilization of G6P, a common substrate for both lipid and glycogen synthesis, markedly induces these anabolic pathways in GSDIa. Thus, excessive lipid accumulation is mainly due to an increase in de novo lipogenesis [11] , [17] , [19] , [21] , [43] . In addition, our results also suggest impaired fatty acid oxidation characterized by a significant decrease in PPARα activity in both the liver and kidneys, in agreement with the decreased mitochondrial oxidative capacity previously observed in GSD1a [44] .…”

“…The first consequence of G6P increase is abnormal accumulation of glycogen in both organs [11] , [14] , [17] , [18] , which has given its name to the disease. However, hepatic and renal lipid metabolism are also markedly altered, characterized by a G6P-dependent increase in de novo lipogenesis and fatty acid chain elongation [10] , [11] , [17] , [19] , [20] , [21] . Thus, GSDI patients suffer from a combined hypertriglyceridemia and hypercholesterolemia associated with hepatic steatosis, characterized by a low-inflammatory state without fibrosis [22] , [23] , [24] and abnormal lipid deposition in the kidney cortex [17] .…”

Translational Metabolism: A multidisciplinary approach towards precision diagnosis of inborn errors of metabolism in the omics era

“…The availability of a number of differentially labeled isotopes has indeed allowed studies to evaluate whole-body glucose, galactose, fatty acid and amino acid metabolism. 65 77 and is comparable to the VLCAD-KO mouse. [78][79][80][81] The fasting-induced hypoglycemia in LCAD KO mice turned out to be caused by an increased requirement of glucose in peripheral tissues leading to rapid glycogen depletion in the liver.…”

“…Ideally, in vitro flux analysis in patients' cells should be followed up by in vivo studies in patients using stable isotopes. The availability of a number of differentially labeled isotopes has indeed allowed studies to evaluate whole‐body glucose, galactose, fatty acid and amino acid metabolism . For example, glucose tracers like [6,6‐ 2 H 2 ]‐glucose have been used to study glucose metabolism in patients with fructose‐1,6‐bisphosphatase deficiency, glycogen storage disease, long‐chain 3‐hydroxyacyl‐CoA dehydrogenase, and medium‐chain acyl‐CoA dehydrogenase (MCAD) deficiency .…”

Dysbiosis, Host Metabolism, and Non-communicable Diseases: Trialogue in the Inborn Errors of Metabolism

“…Diets excessively rich or poor in some nutrients, a common characteristic of dietary intervention in several IEMs, can promote a possible state of dysbiosis with potential systemic effects ( Colonetti et al, 2018 ). Considering that the gut microbiota may influence some specific clinical phenotypes, this paper aims at exploring the possible links between IEMs, with external modulating factors, with the gut microbial community, and the health status of affected individuals ( Reijngoud, 2018 ), also in relation to the eventual presence of non-communicable diseases (NCDs). Moreover, we want to discuss the potential contribution of gut microbiota in the challenging research of new treatments for these complex diseases.…”