“…It is mainly synthesized by the liver, but it can also be produced by other tissues that possess xanthine oxidase activity, such as the intestines, muscles, kidneys, and vascular endothelium . Due to the pseudogenization of the uricase gene during the evolution of hominoid primates, humans among other mammals lost uricase activity, rendering them unable to further oxidize urate to the more water‐soluble compound allantoin . Thus, serum urate (sUA) levels are three to ten times higher in humans than in uricase‐preserving organisms.…”
Trained immunity is a process in which innate immune cells undergo functional reprogramming in response to pathogens or damage‐associated molecules leading to an enhanced non‐specific immune response to subsequent stimulation. While this capacity to respond more strongly to stimuli is beneficial for host defense, in some circumstances it can lead to maladaptive programming and chronic inflammation. Gout is characterized by persistent low‐grade inflammation and is associated with an increased number of comorbidities. Hyperuricemia is the main risk factor for gout and is linked to the development of comorbidities. Several experimental studies have shown that urate can mechanistically alter the inflammatory capacity of myeloid cells, while observational studies have indicated an association of hyperuricemia to a wide spectrum of common adult inflammatory diseases. In this review, we argue that hyperuricemia is a main culprit in the development of the long‐term systemic inflammation seen in gout. We revisit existing evidence for urate‐induced transcriptional and epigenetic reprogramming that could lead to an altered functional state of circulating monocytes consisting in enhanced responsiveness and maladaptive immune responses. By discussing specific functional adaptations of monocytes and macrophages induced by soluble urate or monosodium urate crystals and their contribution to inflammation in vitro and in vivo, we further enforce that urate is a metabolite that can induce innate immune memory and we discuss future research and possible new therapeutic approaches for gout and its comorbidities.
“…It is mainly synthesized by the liver, but it can also be produced by other tissues that possess xanthine oxidase activity, such as the intestines, muscles, kidneys, and vascular endothelium . Due to the pseudogenization of the uricase gene during the evolution of hominoid primates, humans among other mammals lost uricase activity, rendering them unable to further oxidize urate to the more water‐soluble compound allantoin . Thus, serum urate (sUA) levels are three to ten times higher in humans than in uricase‐preserving organisms.…”
Trained immunity is a process in which innate immune cells undergo functional reprogramming in response to pathogens or damage‐associated molecules leading to an enhanced non‐specific immune response to subsequent stimulation. While this capacity to respond more strongly to stimuli is beneficial for host defense, in some circumstances it can lead to maladaptive programming and chronic inflammation. Gout is characterized by persistent low‐grade inflammation and is associated with an increased number of comorbidities. Hyperuricemia is the main risk factor for gout and is linked to the development of comorbidities. Several experimental studies have shown that urate can mechanistically alter the inflammatory capacity of myeloid cells, while observational studies have indicated an association of hyperuricemia to a wide spectrum of common adult inflammatory diseases. In this review, we argue that hyperuricemia is a main culprit in the development of the long‐term systemic inflammation seen in gout. We revisit existing evidence for urate‐induced transcriptional and epigenetic reprogramming that could lead to an altered functional state of circulating monocytes consisting in enhanced responsiveness and maladaptive immune responses. By discussing specific functional adaptations of monocytes and macrophages induced by soluble urate or monosodium urate crystals and their contribution to inflammation in vitro and in vivo, we further enforce that urate is a metabolite that can induce innate immune memory and we discuss future research and possible new therapeutic approaches for gout and its comorbidities.
“…Mammals possessing a functional uricase typically display serum uric acid levels of 10–20 µg/mL. In contrast, uric acid levels are 3 to 10 times higher in apes and humans as a result of parallel nonsense mutations that caused a pseudogenization of the uricase gene during the early Miocene era [3], [4].Fig. 1The most alarming step [80].…”
Graphical abstractUric acid, C5H4N4O3, 7,9-dihydro-1H-purine-2,6,8(3H)-trione, molecular mass 168 Da, is a product of the metabolic breakdown of purine nucleotides (adenine and guanine).
“…Suddenly, fruits were scarce during the winter period. Interestingly, neither humans nor apes hold a functional gene that expresses the enzyme uricase, as in most animals
43 . Uricase degrades uric acid, which is produced by the breakdown of DNA substances from food or body's own cells
44 .…”
During the course of evolution, up until the agricultural revolution, environmental fluctuations forced the human species to develop a flexible metabolism in order to adapt its energy needs to various climate, seasonal and vegetation conditions. Metabolic flexibility safeguarded human survival independent of food availability. In modern times, humans switched their primal lifestyle towards a constant availability of energy-dense, yet often nutrient-deficient, foods, persistent psycho-emotional stressors and a lack of exercise. As a result, humans progressively gain metabolic disorders, such as the metabolic syndrome, type 2 diabetes, non-alcoholic fatty liver disease, certain types of cancer, cardiovascular disease and Alzheimer´s disease, wherever the sedentary lifestyle spreads in the world. For more than 2.5 million years, our capability to store fat for times of food shortage was an outstanding survival advantage. Nowadays, the same survival strategy in a completely altered surrounding is responsible for a constant accumulation of body fat. In this article, we argue that the metabolic epidemic is largely based on a deficit in metabolic flexibility. We hypothesize that the modern energetic inflexibility, typically displayed by symptoms of neuroglycopenia, can be reversed by re-cultivating suppressed metabolic programs, which became obsolete in an affluent environment, particularly the ability to easily switch to ketone body and fat oxidation. In a simplified model, the basic metabolic programs of humans’ primal hunter-gatherer lifestyle are opposed to the current sedentary lifestyle. Those metabolic programs, which are chronically neglected in modern surroundings, are identified and conclusions for the prevention of chronic metabolic diseases are drawn.
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