Cell metabolism最新文献

The peripheral nervous system harbors a remarkable potential to regenerate after acute nerve trauma. Full functional recovery, however, is rare and critically depends on peripheral nerve Schwann cells that orchestrate breakdown and resynthesis of myelin and, at the same time, support axonal regrowth. How Schwann cells meet the high metabolic demand required for nerve repair remains poorly understood. We here report that nerve injury induces adipocyte to glial signaling and identify the adipokine leptin as an upstream regulator of glial metabolic adaptation in regeneration. Signal integration by leptin receptors in Schwann cells ensures efficient peripheral nerve repair by adjusting injury-specific catabolic processes in regenerating nerves, including myelin autophagy and mitochondrial respiration. Our findings propose a model according to which acute nerve injury triggers a therapeutically targetable intercellular crosstalk that modulates glial metabolism to provide sufficient energy for successful nerve repair.

In a recent Presidential Advisory report, the American Heart Association (AHA) defined cardiovascular-kidney-metabolic (CKM) syndrome as a spectrum of pathology associated with dysfunctional or excess adiposity and leading to adverse cardiovascular outcomes. Implementing the guidelines set forth by the AHA has the potential to improve population-wide CKM health.

Mammalian target of rapamycin complex 1 (mTORC1) monitors cellular amino acid changes for function, but the molecular mediators of this process remain to be fully defined. Here, we report that depletion of cellular amino acids, either alone or in combination, leads to the ubiquitination of mTOR, which inhibits mTORC1 kinase activity by preventing substrate recruitment. Mechanistically, amino acid depletion causes accumulation of uncharged tRNAs, thereby stimulating GCN2 to phosphorylate FBXO22, which in turn accrues in the cytoplasm and ubiquitinates mTOR at Lys2066 in a K27-linked manner. Accordingly, mutation of mTOR Lys2066 abolished mTOR ubiquitination in response to amino acid depletion, rendering mTOR insensitive to amino acid starvation both in vitro and in vivo. Collectively, these data reveal a novel mechanism of amino acid sensing by mTORC1 via a previously unknown GCN2-FBXO22-mTOR pathway that is uniquely controlled by uncharged tRNAs.

Substantial divergence in cardio-metabolic risk, muscle size, and performance exists between men and women. Considering the pivotal role of skeletal muscle in human physiology, we investigated and found, based on RNA sequencing (RNA-seq), that differences in the muscle transcriptome between men and women are largely related to testosterone and estradiol and much less related to genes located on the Y chromosome. We demonstrate inherent unique, sex-dependent differences in muscle transcriptional responses to aerobic, resistance, and combined exercise training in young and older cohorts. The hormonal changes with age likely explain age-related differential expression of transcripts. Furthermore, in primary human myotubes we demonstrate the profound but distinct effects of testosterone and estradiol on amino acid incorporation to multiple individual proteins with specific functions. These results clearly highlight the potential of designing exercise programs tailored specifically to men and women and have implications for people who change gender by altering their hormone profile.

Amino acid metabolism has been actively investigated as a potential target for antitumor therapy, but how it may alter the response to genotoxic chemotherapy remains largely unknown. Here, we report that the depletion of fumarylacetoacetate hydrolase (FAH), an enzyme that catalyzes the final step of tyrosine catabolism, reduced chemosensitivity in epithelial ovarian cancer (EOC). The expression level of FAH correlated significantly with chemotherapy efficacy in patients with EOC. Mechanistically, under genotoxic chemotherapy, FAH is oxidized at Met308 and translocates to the nucleus, where FAH-mediated tyrosine catabolism predominantly supplies fumarate. FAH-produced fumarate binds directly to REV1, resulting in the suppression of translesion DNA synthesis (TLS) and improved chemosensitivity. Furthermore, in vivo tyrosine supplementation improves sensitivity to genotoxic chemotherapeutics and reduces the occurrence of therapy resistance. Our findings reveal a unique role for tyrosine-derived fumarate in the regulation of TLS and may be exploited to improve genotoxic chemotherapy through dietary tyrosine supplementation.

The PNPLA3 I148M variant is the major genetic risk factor for all stages of fatty liver disease, but the underlying pathophysiology remains unclear. We studied the effect of this variant on hepatic metabolism in homozygous carriers and non-carriers under multiple physiological conditions with state-of-the-art stable isotope techniques. After an overnight fast, carriers had higher plasma β-hydroxybutyrate concentrations and lower hepatic de novo lipogenesis (DNL) compared to non-carriers. After a mixed meal, fatty acids were channeled toward ketogenesis in carriers, which was associated with an increase in hepatic mitochondrial redox state. During a ketogenic diet, carriers manifested increased rates of intrahepatic lipolysis, increased plasma β-hydroxybutyrate concentrations, and decreased rates of hepatic mitochondrial citrate synthase flux. These studies demonstrate that homozygous PNPLA3 I148M carriers have hepatic mitochondrial dysfunction leading to reduced DNL and channeling of carbons to ketogenesis. These findings have implications for understanding why the PNPLA3 variant predisposes to progressive liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an unabated risk factor for end-stage liver diseases with no available therapies. Dysregulated immune responses are critical culprits of MASLD pathogenesis. Independent contributions from either the innate or adaptive arms of the immune system or their unidirectional interplay are commonly studied in MASLD. However, the bidirectional communication between innate and adaptive immune systems and its impact on MASLD remain insufficiently understood. Given that both innate and adaptive immune cells are indispensable for the development and progression of inflammation in MASLD, elucidating pathogenic contributions stemming from the bidirectional interplay between these two arms holds potential for development of novel therapeutics for MASLD. Here, we review the immune cell types and bidirectional pathways that influence the pathogenesis of MASLD and highlight potential pharmacologic approaches to combat MASLD based on current knowledge of this bidirectional crosstalk.

A high-fat diet (HFD) promotes metastasis through increased uptake of saturated fatty acids (SFAs). The fatty acid transporter CD36 has been implicated in this process, but a detailed understanding of CD36 function is lacking. During matrix detachment, endoplasmic reticulum (ER) stress reduces SCD1 protein, resulting in increased lipid saturation. Subsequently, CD36 is induced in a p38- and AMPK-dependent manner to promote preferential uptake of monounsaturated fatty acids (MUFAs), thereby maintaining a balance between SFAs and MUFAs. In attached cells, CD36 palmitoylation is required for MUFA uptake and protection from palmitate-induced lipotoxicity. In breast cancer mouse models, CD36-deficiency induced ER stress while diminishing the pro-metastatic effect of HFD, and only a palmitoylation-proficient CD36 rescued this effect. Finally, AMPK-deficient tumors have reduced CD36 expression and are metastatically impaired, but ectopic CD36 expression restores their metastatic potential. Our results suggest that, rather than facilitating HFD-driven tumorigenesis, CD36 plays a supportive role by preventing SFA-induced lipotoxicity.

Weight regain is a major challenge in the long-term management of obesity; however, the underlying mechanisms remain unclear. Zhou et al. found that bone-marrow-derived CD7⁺ monocytes respond to fluctuating nutritional stress and suppress weight regain by promoting beige fat thermogenesis.

Emerging studies have addressed the tumor-promoting role of fructose in different cancers. The effects and pathological mechanisms of high dietary fructose on hepatocellular carcinoma (HCC) remain unclear. Here, we examined the effects of fructose supplementation on HCC progression in wild-type C57BL/6 mice using a spontaneous and chemically induced HCC mouse model. We show that elevated uridine diphospho-N-acetylglucosamine (UDP-GlcNAc) and O-GlcNAcylation levels induced by high dietary fructose contribute to HCC progression. Non-targeted metabolomics and stable isotope tracing revealed that under fructose treatment, microbiota-derived acetate upregulates glutamine and UDP-GlcNAc levels and enhances protein O-GlcNAcylation in HCC. Global profiling of O-GlcNAcylation revealed that hyper-O-GlcNAcylation of eukaryotic elongation factor 1A1 promotes cell proliferation and tumor growth. Targeting glutamate-ammonia ligase or O-linked N-acetylglucosamine transferase (OGT) remarkably impeded HCC progression in mice with high fructose intake. We propose that high dietary fructose promotes HCC progression through microbial acetate-induced hyper-O-GlcNAcylation.