Nature metabolism最新文献

Choline is an essential micronutrient critical for cellular and organismal homeostasis. As a core component of phospholipids and sphingolipids, it is indispensable for membrane architecture and function. Additionally, choline is a precursor for acetylcholine, a key neurotransmitter, and betaine, a methyl donor important for epigenetic regulation. Consistent with its pleiotropic role in cellular physiology, choline metabolism contributes to numerous developmental and physiological processes in the brain, liver, kidney, lung and immune system, and both choline deficiency and excess are implicated in human disease. Mutations in the genes encoding choline metabolism proteins lead to inborn errors of metabolism, which manifest in diverse clinical pathologies. While the identities of many enzymes involved in choline metabolism were identified decades ago, only recently has the field begun to understand the diverse mechanisms by which choline availability is regulated and fuelled via metabolite transport/recycling and nutrient acquisition. This review provides a comprehensive overview of choline metabolism, emphasizing emerging concepts and their implications for human health and disease.

Transmembrane-6 superfamily member 2 (TM6SF2) regulates hepatic fat metabolism and is associated with metabolic dysfunction-associated steatohepatitis (MASH). TM6SF2 genetic variants are associated with steatotic liver disease. The pathogenesis of MASH involves genetic factors and gut microbiota alteration, yet the role of host–microbe interactions in MASH development remains unclear. Here, we discover that mice with intestinal epithelial cell-specific knockout of Tm6sf2 (Tm6sf2^ΔIEC) develop MASH, accompanied by impaired intestinal barrier and microbial dysbiosis. Transplanting stools from Tm6sf2^ΔIEC mice induces steatohepatitis in germ-free recipient mice, whereas MASH is alleviated in Tm6sf2^ΔIEC mice co-housed with wild-type mice. Mechanistically, Tm6sf2-deficient intestinal cells secrete more free fatty acids by interacting with fatty acid-binding protein 5 to induce intestinal barrier dysfunction, enrichment of pathobionts, and elevation of lysophosphatidic acid (LPA) levels. LPA is translocated from the gut to the liver, contributing to lipid accumulation and inflammation. Pharmacological inhibition of the LPA receptor suppresses MASH in both Tm6sf2^ΔIEC and wild-type mice. Hence, modulating microbiota or blocking the LPA receptor is a potential therapeutic strategy in TM6SF2 deficiency-induced MASH.

Nucleotide availability is crucial for DNA replication and repair; however, the coordinating mechanisms in vivo remain unclear. Here, we show that the circadian clock in the liver controls the activity of the pentose phosphate pathway (PPP) to support de novo nucleotide biosynthesis for DNA synthesis demands. We demonstrate that disrupting the hepatic clock by genetic manipulation or mistimed feeding impairs PPP activity in male mice, leading to nucleotide imbalance. Such defects not only elicit DNA replication stress to limit liver regeneration after resection but also allow genotoxin-induced hepatocyte senescence and STING signalling-dependent inflammation. Mechanistically, the molecular clock activator BMAL1 synergizes with hypoxia-inducible factor-1α (HIF-1α) to regulate the transcription of the PPP rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD), which is enhanced during liver regeneration. Overexpressing G6PD restores the compromised regenerative capacity of the BMAL1- or HIF-1α-deficient liver. Moreover, boosting G6PD expression genetically or through preoperative intermittent fasting potently facilitates liver repair in normal mice. Hence, our findings highlight the physiological importance of the hepatic clock and suggest a promising pro-regenerative strategy.

Nutrient sensors allow cells to adapt their metabolisms to match nutrient availability by regulating metabolic pathway expression. Many such sensors are cytosolic receptors that measure intracellular nutrient concentrations. One might expect that inducing the metabolic pathway that degrades a nutrient would reduce intracellular nutrient levels, destabilizing induction. However, in the galactose-responsive (GAL) pathway of Saccharomyces cerevisiae, we find that induction is stabilized by flux sensing. Previously proposed mechanisms for flux sensing postulate the existence of metabolites whose concentrations correlate with flux. The GAL pathway flux sensor uses a different principle: the galactokinase Gal1p both performs the first step in GAL metabolism and reports on flux by signalling to the GAL repressor, Gal80p. Both Gal1p catalysis and Gal1p signalling depend on the concentration of the Gal1p–GAL complex and are therefore directly correlated. Given the simplicity of this mechanism, flux sensing is probably a general feature throughout metabolic regulation.

Obesity is a global health problem related to the Western lifestyle. Lifestyle is biological but also non-biological, and so requires more than studies of diet, exercise and mechanisms of cellular metabolism. The recent Perspective by Magkos et al.¹ provides an excellent overview of leading causal models in metabolic obesity research and new areas for future exploration. Specifically, they contrast the energy balance model (EBM) and the carbohydrate–insulin model (CIM). The latter can be considered a version of the fuel partitioning model (FPM)². We draw attention to the need for holistic, interdisciplinary approaches, with potential new ontological perspectives, to explain and combat obesity beyond what is currently considered within said existing biological models. The World Health Organization’s 1946 definition of health as “… complete physical, mental, and social well-being” points to such a holistic understanding of health. Over the past decades, spirituality has been suggested as a necessary fourth dimension of human health³. Although Magkos et al. include “psychosocial” among “other factors” in their model, they hardly discuss mental or social factors and leave out spirituality.

Drawing on experience from palliative care, spirituality is widely defined as the “dynamic and intrinsic aspect of humanity through which persons seek ultimate meaning, purpose, and transcendence, and experience relationship to self, family, others, community, society, nature, and the significant or sacred. Spirituality is expressed through beliefs, values, traditions, and practices”⁵. Recent epidemiological studies show robust associations between spirituality and health outcomes⁶. Such relations are challenging to explain entirely by altered metabolism or psychosocial factors, and the observed effects may be partly determined by independent effects of spirituality⁷. The majority of the global population expresses faith convictions in some form (spiritual, religious, secular and/or existential)^6,7,8. Spiritual needs and expressions are common, including in modern, secular cultures⁸. Hence, personal or communal spirituality may influence how people understand and relate to their body, food and eating⁹. Beyond psychosocial issues, existential anxiety may stimulate appetite and fat storage, in line with conventional EBM and FPM theories.

Resting natural killer (NK) cells display immediate effector functions after recognizing transformed or infected cells. The environmental nutrients and metabolic requirements to sustain these functions are not fully understood. Here, we show that NK cells rely on the use of extracellular pyruvate to support effector functions, signal transduction and cell viability. Glucose-derived carbons do not generate endogenous pyruvate. Consequently, NK cells import extracellular pyruvate that is reduced to lactate to regenerate glycolytic NAD⁺ and is oxidized in the tricarboxylic acid (TCA) cycle to produce ATP. This supports serine production through phosphoglycerate dehydrogenase, a pathway required for optimal proliferation following cytokine stimulation but dispensable for effector functions. In addition, like mouse NK cells, human NK cells rely on a citrate–malate configuration of the TCA cycle that is not fed by glutamine. Moreover, supraphysiologic pyruvate concentrations dose-dependently increase the effector functions of NK cells. Overall, this study highlights the role of exogenous pyruvate in NK cell biology, providing knowledge that could be exploited to boost NK cell potential in therapeutic settings.

Nutrient availability strongly affects intestinal homeostasis. Here, we report that low-protein (LP) diets decrease amino acids levels, impair the DNA damage response (DDR), cause DNA damage and exacerbate inflammation in intestinal tissues of male mice with inflammatory bowel disease (IBD). Intriguingly, loss of nuclear fragile X mental retardation-interacting protein 1 (NUFIP1) contributes to the amino acid deficiency-induced impairment of the DDR in vivo and in vitro and induces necroptosis-related spontaneous enteritis. Mechanistically, phosphorylated NUFIP1 binds to replication protein A2 (RPA32) to recruit the ataxia telangiectasia and Rad3-related (ATR)–ATR-interacting protein (ATRIP) complex, triggering the DDR. Consistently, both reintroducing NUFIP1 but not its non-phospho-mutant and inhibition of necroptosis prevent bowel inflammation in male Nufip1 conditional knockout mice. Intestinal inflammation and DNA damage in male mice with IBD can be mitigated by NUFIP1 overexpression. Moreover, NUFIP1 protein levels in the intestine of patients with IBD were found to be significantly decreased. Conclusively, our study uncovers that LP diets contribute to intestinal inflammation by hijacking NUFIP1–DDR signalling and thereby activating necroptosis.