Acetyl-coenzyme A (acetyl-CoA) is a central metabolite that underpins energy production, biosynthesis, and protein acetylation. A recent study by Zhang et al. published in Nature reveals a striking non-canonical role for cytosolic acetyl-CoA as a direct small-molecule ligand for the nucleotide-binding oligomerization domain (NOD)-like receptor NLRX1, stabilizing its autoinhibited state and thereby tuning receptor mediated mitophagy.
Xianda Ma , Qiyi Yu , Zheng Kuang·30 Jan 2026
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The intestine is more than a digestive organ. It is a system under circadian control, where cellular renewal, barrier integrity, absorption, immunity, and microbial ecology are orchestrated in time. Emerging evidence reveals that circadian rhythms not only regulate the daily turnover of intestinal epithelium but also fine-tune digestive enzyme expression, mucosal defense, and gut hormone secretion. These processes are driven by core clock proteins and synchronized by feeding cues, neural signals, and microbial metabolites. The gut microbiota consists of essential symbionts that themselves exhibit diurnal oscillations in composition and function, in turn feeding back to modulate host circadian pathways. Disruption of this host−microbiota temporal alignment, as occurs with jet lag, shift work, or high-fat diets, impairs intestinal homeostasis and elevates risk for inflammation, infection, and metabolic disorders. This review integrates evidence from mouse, zebrafish, fly, and human studies to highlight the rhythmic regulation of gut physiology, emphasizing how coordination between the host clock and microbiota sustains health. Viewing the gut as a circadian conductor underscores new opportunities for chronotherapy and microbiota-targeted interventions.
Metabolic dysfunction-associated steatotic liver disease (MASLD), characterized by hepatic steatosis, inflammation, and fibrosis, has reached epidemic proportions globally. Emerging evidence highlights a close association between amino acid metabolic dysregulation and MASLD pathogenesis, however, the precise mechanisms remain elusive. In this study, we identify pyrroline-5-carboxylate synthase (P5CS), a pivotal enzyme in proline biosynthesis, as a critical regulator of hepatic proline production and a key driver of MASLD progression. Based on comprehensive analysis of clinical samples from MASLD patients and experimental mouse models, we demonstrate that elevated hepatic and plasma proline levels, resulting from increased P5CS expression, are strongly correlated with disease severity. Genetic overexpression of P5CS in the livers of mice exacerbates diet-induced MASLD, whereas its knockdown exhibits protective profiles. Notably, proline supplementation abolishes the beneficial effects of P5CS knockdown, confirming the causal role of proline overproduction in MASLD pathogenesis. Mechanistically, P5CS-mediated proline accumulation impairs mitochondrial function, thereby disrupting fatty acid oxidation and promoting hepatic lipid accumulation. Pharmacological inhibition of P5CS activity could restore mitochondrial capacity. Thus, our findings establish P5CS-regulated proline metabolism as a novel pathogenic mechanism in MASLD and provides a potential approach for MASLD therapy.
Daniel P Phillips , Sharon E Mitchell , Davina Derous , John R Speakman·12 Feb 2026
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Alternative splicing (AS) involves production of several different RNA molecules from a single pre-mRNA. Calorie restriction (CR) is a sustained calorie deficit without malnutrition which extends health and lifespan. AS is dysregulated in aging but less so following CR, suggesting a role for AS in the beneficial effects of CR. To test the hypothesis that AS is involved in the CR response and explore its tissue specificity, male C57BL/6 mice were exposed to three months of graded CR (0 − 40% at 10% increments) and RNA-seq data from six tissues (epididymal white adipose tissue [eWAT], liver, hypothalamus, gastrocnemius muscle, testes, and stomach) were analyzed to provide a multi-tissue characterization of differential AS (DAS). The number of differentially expressed splicing regulators increased with CR level in all tissues but primarily muscle, eWAT and liver. The total number of DAS genes also increased with increasing CR level and was largely tissue-specific. Most DAS genes were not differentially expressed. DAS was functionally integrated across tissues with the same processes being overrepresented: namely, mitochondria and oxidative phosphorylation, transcription and translation, and quality-checking and degradation of RNA and especially proteins. This study demonstrates that short-term CR evokes a functionally integrated cross-tissue AS response in mice that is largely independent of expression changes.
Jiarui Zhang , Zehui Cao , Jinbao Yang , Kuo Zhu , Shuai Liu , Weijie Liu , Jin Lu , Hongfang Zhao , Wei Dai , Chunmei Chang , Haobin Ye , Xingrong Du , Qi Wang , Binghua Jiang , Sijia Wang , Li Jin , Tongjin Zhao , Peng Li , Antonio Vidal-Puig , Yuanting Zheng , Leming Shi , Linzhang Huang·19 Dec 2025
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Glycine, a non-essential amino acid, has been linked to improved metabolic health and enhanced insulin secretion, yet its mechanistic role in β-cell function remains poorly defined. Here, we identify a glycine–GLRA1–calmodulin signaling axis that regulates endoplasmic reticulum (ER) calcium homeostasis to support insulin biosynthesis and β-cell survival. Dietary glycine deficiency impairs insulin secretion, reduces islet mass, and worsens glucose intolerance, while overexpression of serine hydroxymethyltransferase 2 (Shmt2), a key glycine biosynthetic enzyme, increases circulating glycine, enhances insulin output, and improves glucose control. Conversely, β-cell-specific deletion of Glra1 phenocopies glycine deficiency, disrupting ER calcium dynamics, amplifying ER stress, and impairing insulin gene expression and secretion. Mechanistically, GLRA1 interacts with calmodulin to sustain ER calcium levels and alleviate ER stress, preserving β-cell viability under metabolic stress. Human genetic and transcriptomic analyses reveal that GLRA1 expression and variants are associated with insulin secretion and glycemic traits, underscoring clinical relevance. These findings establish glycine as a signaling metabolite that activates a receptor–calcium axis to maintain β-cell function, offering a mechanistic rationale for targeting GLRA1 or dietary glycine in diabetes therapy.
Kai Luo , Xiyue Shen , Siyu Wang , Fang Li , Yierxiati Jianggewaer , Weiping Sun , Zhongbing Lu·04 Dec 2025
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Under nutrient deprivation conditions, the liver maintains systemic energy homeostasis by mobilizing lipid reserves, a process often accompanied by hepatic lipid accumulation. Dimethylarginine dimethylaminohydrolase 1 (DDAH1), a key metabolizing enzyme for asymmetric dimethylarginine (ADMA), has been demonstrated to exert a protective effect in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), yet its role in fasting-induced hepatic metabolic adaptation remains incompletely elucidated. In this study, we explored the function of DDAH1 in fasting-induced liver lipid accumulation using hepatocyte-specific Ddah1 knockout (Ddah1 HKO) mice. Compared with control mice (Ddah1 f/f), Ddah1 HKO mice exhibited significantly attenuated hepatic steatosis after fasting. Lipidomic analysis of the liver revealed decreased levels of most lipid species (e.g., triglycerides and free fatty acids) in Ddah1 HKO mice. Further mechanistic studies demonstrated that Ddah1 deletion downregulated the protein expression of hepatic fatty acid binding protein 1 (FABP1) and activated the AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) signaling pathway, thereby enhancing autophagic flux and promoting lipid droplet degradation under fasting conditions. Hepatic overexpression of FABP1 reversed the anti-steatotic phenotype of Ddah1 HKO mice, while treatment with the AMPK inhibitor Compound C suppressed autophagy and increased hepatic lipid accumulation. Additionally, overexpression of DDAH1 in hepatocytes exacerbated hepatic steatosis in fasted mice, coinciding with FABP1 upregulation and autophagy inhibition. Collectively, this study reveals that DDAH1 plays a critical role in hepatic lipid metabolism under fasting conditions by modulating FABP1 expression and AMPK/mTOR-mediated autophagy.
Yanru Chen, Mengshan Ni, Yufei Chen, Chongrong Shen, Yaogan Luo, Huibin Lin, Juan Zhang, Huajie Dai, Aibo Gao, Muye Tong, Yinmeng Zhu, Yan Lu, Jie Hong, Weiqiong Gu, Rong Zeng, Weiqing Wang, Xu Lin, Min Xu, Ruixin Liu, Guang Ning, Jiqiu Wang·13 Nov 2025
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Precision nutrition is pivotal to preventing cardiometabolic diseases. However, almost no single blood biomarker capable of predicting the metabolic benefits of specific dietary patterns has yet been identified. Here, we revealed the associations of plasma levels of the secreted protein acidic and rich in cysteine (SPARC), an inflammatory factor highly expressed in fat tissues, and insulin sensitivity improvement in a 6-month randomized controlled, calorie-restricted feeding trial recruiting 235 Chinese adults with overweight/obesity and prediabetes: the Mediterranean diet (MD) group (n = 81), the traditional Jiangnan diet (TJD) group (n = 81), and the control diet (CD) group (n = 73). The 1-h post-glucose loading plasma SPARC levels (SPARC-1H) decreased significantly from baseline to 3 months and 6 months in the MD group, whereas no significant changes were observed in the TJD or CD groups. Further analyses revealed that the individuals with higher baseline SPARC-1H levels were associated with fewer improvements in fasting insulin (β ± SE: 1.54 ± 0.43; P = 0.0007), fasting glucose (0.10 ± 0.04; P = 0.013), the homeostasis model assessment of insulin resistance (HOMA-IR, 0.47 ± 0.12; P = 0.0002), and the homeostasis model assessment of β-cell function (HOMA-β, 7.63 ± 3.27; P = 0.023) after 6 month in MD group. Moreover, baseline SPARC-1H levels were positively correlated with changes in lipidomic profiles, including three alkenylphosphatidylethanolamines (PE(P)s), which potentially mediate the cardiometabolic benefits of the MD group. No significant associations were observed in the other two diet groups. Our findings suggest postprandial SPARC as a predictor for the metabolic benefits of MD, offering a potential biomarker for individualized nutrition interventions against cardiometabolic diseases.
