Since Franz Schardinger first identified xanthine dehydrogenase (XDH) 123 years ago, the
oxidation of purines to uric acid via the XDH pathway has been recognized as a central route in
purine metabolism. Two recent studies now describe a previously unknown anaerobic uric-acid
degradation pathway in gut bacteria, highlighting its contribution to systemic urate homeostasis
and its therapeutic promise for hyperuricemia and gout.
Lauren Palluth, Joseph S Takahashi, Carla B Green·29 Aug 2025
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The hierarchical relationship between the core circadian clock of the suprachiasmatic nucleus and peripheral clocks throughout the body is tightly regulated. Nicotinamide adenine dinucleotide phosphate (NADP(H)) is a rhythmic cofactor used in hundreds of metabolic reactions. The cellular NADP(H) pool is not only regulated by several clock-controlled enzymes, but also responsive to peripheral “zeitgebers” such as food intake and oxidative stress. This positions NADP(H) as a potential harbinger between core and peripheral metabolic rhythms. While discussion in recent years has focused on its unphosphorylated counterpart, NAD(H), this review aims to highlight the roles of NADP(H) in circadian metabolism. This review discusses the multilayered regulation of cellular NADP(H), how the total pool size, redox ratio, and rhythmicity of NADP(H) impact core and peripheral rhythms, and how disruption of its rhythmic regulation can lead to metabolic disease.
Lu Zhang, Jing Chen, Si-Jia Ge, Tian-Yi Huang, Xiang Shi, Yu-Yan Chen, Cui-Hua Lu·08 Oct 2025
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The gut commensal bacterium Akkermansia muciniphila (AKK) has emerged as a candidate for treating liver disorders, yet its therapeutic potential in liver fibrosis remains poorly defined. Here, using a carbon tetrachloride (CCl4)-induced murine model, we show that AKK administration markedly attenuates collagen deposition, inflammation, and hepatic injury. AKK restored intestinal barrier integrity, reshaped microbial composition, and enhanced propionic acid transport from the gut to the liver, leading to suppression of hepatic stellate cell activation. Multi-omics profiling revealed that AKK enriched propionate-producing taxa and upregulated key metabolic enzymes, thereby elevating hepatic propionate levels. Supplementation with propionic acid alone recapitulated AKK’s benefits, improving liver function, alleviating extracellular matrix accumulation, and activating the Keap1–Nrf2 antioxidant pathway. Together, our findings identify a microbiota–metabolite axis in which AKK counters liver fibrosis by enhancing propionate-mediated antioxidant regulation, highlighting its therapeutic promise for chronic liver disease.
Dong Yu, Xiao Yang, Xiaonan Zhang, Xiaoxin Wang, Zicheng Pu, Ai Mi, Liyuan Ran, Fang Zhang, Bin Liang, Yingjie Wu·28 Oct 2025
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Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the most prevalent chronic liver disease worldwide, affecting both obese and non-obese individuals. While the reduced levels of circulating growth hormone (GH) and insulin-like growth factor 1 (IGF-1) have been consistently observed in patients with hepatic steatosis, the molecular role of hepatic growth hormone receptor (GHR) in MAFLD pathogenesis remains unclear. In this study, we established a liver-specific Ghr knockout (LGHRKO) mouse model that faithfully recapitulates non-obese MAFLD, characterized by hepatomegaly, elevated serum lipids and transaminases, and pronounced hepatic lipid accumulation, all occurring in the absence of obesity or increased adiposity. Mechanistically, LGHRKO livers displayed enhanced lipogenesis, impaired lipolysis, and upregulated cluster of differentiation 36 (CD36) expression, thereby driving hepatic lipid deposition. Single-cell RNA sequencing (scRNA-seq) further revealed hepatocyte-specific transcriptional alterations, including activation of lipid metabolic pathways and dysregulation of autophagy-related processes, providing insights into the cellular mechanisms underlying disease progression. Complementary human genetic analyses, including two-sample Mendelian randomization (MR) and genome-wide association studies (GWAS), demonstrated a causal relationship between impaired GH–IGF signaling and susceptibility to MAFLD, thereby bridging experimental observations with human disease risk. Collectively, our findings identify hepatic GHR deficiency as a key driver of non-obese MAFLD, establish LGHRKO mice as a valuable model for mechanistic and therapeutic studies, and underscore the translational significance of GH–IGF signaling in metabolic liver disease.
Dysregulated autophagy contributes to liver steatosis, yet its regulation under distinct metabolic contexts remains poorly defined. Here, we identify bile acids (BAs) as critical modulators of hepatic autophagy. Circulating BA levels are elevated in human subjects with liver steatosis and independently associated with increased hepatic steatosis risk. High-fat diet (HFD) feeding increases circulating BA levels, while simultaneously reducing hepatic autophagic flux in mice, whereas pharmacological inhibition of farnesoid X receptor (FXR) enhances autophagy and alleviates steatosis in the livers of HFD-fed mice. Mechanistically, circulating bile acids promote hepatic acetyl-CoA production through FXR-induced acyl-CoA oxidase 1 (ACOX1), which in turn suppresses autophagy by increasing the mechanistic target of rapamycin complex 1 (mTORC1) signaling. Similar to HFD feeding, prolonged fasting elevates BA levels and hepatic lipid accumulation, while concurrently upregulating hepatic miR-378, a positive regulator of BA synthesis. Although miR-378 exerts a cell-autonomous pro-autophagic effect during short-term fasting, it paradoxically drives lipid accumulation by suppressing hepatic autophagy via BA/FXR/ACOX1/acetyl-CoA axis in a non-cell-autonomous manner during either HFD feeding or prolonged fasting when BA action becomes considerable. Together, our study uncovers BAs as previously unrecognized inhibitor of hepatic autophagy during prolonged fasting and in metabolic dysfunction-associated steatosis liver disease (MASLD), providing novel insights into context-dependent autophagic regulation of hepatic lipid metabolism and potential therapeutic strategies for MASLD.
