Metabolism
Abstract
Oxidative stress driven by malfunctioning respiratory complex I (RC-I) is a crucial pathogenic factor in liver ischemia/reperfusion (I/R) injury. This study investigates the role of alkaline ceramidase 3 (ACER3) and its unsaturated long-chain ceramide (CER) substrates in regulating liver I/R injury through RC-I. Our findings demonstrated that I/R upregulated ACER3/Acer3 and decreased unsaturated long-chain CER levels in human and mouse livers. Both global and hepatocyte-specific Acer3 ablation, as well as treatment with CER(d18:1/18:1), led to a significant increase of CER(d18:1/18:1) levels in the liver, which mitigated the I/R-induced hepatocyte damage and inflammation in mice. Mechanistically, Acer3 modulated CER(d18:1/18:1) levels in mitochondria-associated membranes and endoplasmic reticulum (ER), thereby influencing the transport of CER(d18:1/18:1) from ER to mitochondria. Acer3 ablation and CER(d18:1/18:1) treatment elevated CER(d18:1/18:1) in mitochondria, where CER(d18:1/18:1) bound to the RC-I subunit Ndufa6 to inactivate RC-I and reduced reactive oxygen species production in the I/R-injured mouse liver. These findings underscore the role of CER(d18:1/18:1)-Ndufa6 interaction in suppressing RC-I-mediated oxidative-stress-driven pathogenesis in liver I/R Injury.
Authors
Kai Wang, Leyi Liao, Hanbiao Liang, Pengxiang Huang, Qingping Li, Baoxiong Zhuang, Chen Xie, Xiangyue Mo, Xuesong Deng, Jieyuan Li, Yang Lei, Minghui Zeng, Cungui Mao, Ruijuan Xu, Cuiting Liu, Xianqiu Wu, Jie Zhou, Biao Wang, Yiyi Li, Chuanjiang Li
Abstract
Biliary atresia (BA) is a pediatric liver disease that often necessitates parenteral nutrition (PN) to support growth due to impaired liver function. While soy oil lipid emulsions (SLE) are commonly used in PN, they may contribute to cholestatic liver injury. In contrast, mixed oil lipid emulsions (MLE) show promise in preventing cholestasis in non-BA infants, potentially by restoring bile flow. However, their effectiveness in cases of complete bile duct obstruction, as seen in BA, remains uncertain. To explore the potential benefits of MLE in BA, we utilized a neonatal pig model of bile duct ligation (BDL). Pigs underwent either BDL or sham surgery and were subsequently fed either MLE or SLE via PN, or enterally with formula. The MLE-BDL pigs exhibited significantly greater weight gain compared to those fed SLE or formula enterally. Additionally, MLE-BDL pigs showed higher serum bile acid and gamma-glutamyl transferase concentrations compared to SLE-BDL pigs. However, no significant differences in liver injury, assessed by ductular reaction or fibrosis, were observed between MLE- and SLE-BDL pigs. Based on weight gain alone, MLE may be a superior lipid emulsion for use in neonates with obstructive cholestasis.
Authors
Greg Guthrie, Caitlin Vonderohe, Valeria Meléndez Hebib, Barbara Stoll, Douglas Burrin
Citation Information: JCI Insight. 2025;10(7):e179990. https://doi.org/10.1172/jci.insight.179990.
Abstract
Metabolic dysfunction–associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide for which there is only one approved treatment. Adenosine monophosphate–activated protein kinase (AMPK) is an interesting therapeutic target since it acts as a central regulator of cellular metabolism. Despite efforts to target AMPK, no direct activators have yet been approved for treatment of this disease. This study investigated the effect of the AMPK activator ATX-304 in a preclinical mouse model of progressive fatty liver disease. The data demonstrated that ATX-304 diminishes body fat mass, lowers blood cholesterol levels, and mitigates general liver steatosis and the development of liver fibrosis, but with pronounced local heterogeneities. The beneficial effects of ATX-304 treatment were accompanied by a shift in the liver metabolic program, including increased fatty acid oxidation, reduced lipid synthesis, as well as remodeling of cholesterol and lipid transport. We also observed variations in lipid distribution among liver lobes in response to ATX-304, and a shift in the zonal distribution of lipid droplets upon treatment. Taken together, our data suggested that ATX-304 holds promise as a potential treatment for MASLD.
Authors
Emanuel Holm, Isabeau Vermeulen, Saba Parween, Ana López-Pérez, Berta Cillero-Pastor, Michiel Vandenbosch, Silvia Remeseiro, Andreas Hörnblad
Abstract
Metastatic outgrowth in distant microscopic niches requires sufficient nutrients, including fatty acids (FAs), to support tumor growth and to generate an immunosuppressive tumor microenvironment (TME). However, despite the important role of FAs in metastasis, the regulation of FA supply in metastatic niches has not been defined. In this report, we show that tumor endothelium actively promotes outgrowth and restricts anti-tumor cytolysis by transferring FA into developing metastatic tumors. We describe a process of transendothelial FA delivery via endosomes that requires mTORC1 activity. Thus, endothelial-specific targeted deletion of Raptor (RptorECKO), a unique component of the mTORC1 complex, significantly reduced metastatic tumor burden that was associated with improved markers of T cell cytotoxicity. Low dose everolimus that selectively inhibited endothelial mTORC1 improves immune checkpoint responses in metastatic disease models. This work reveals the importance of transendothelial nutrient delivery to the TME, highlighting a future target for therapeutic development.
Authors
Deanna N Edwards, Shan Wang, Kelby Kane, Wenqiang Song, Laura C. Kim, Verra M. Ngwa, Yoonha Hwang, Kevin C. Ess, Mark R. Boothby, Jin Chen
Abstract
RESULTS. Participants with CAD (n = 723) had 12% higher mean relative levels of nHDLox compared with those with invasively excluded CAD (n = 502, P < 0.001). Patients presenting with symptoms of an ACS had the highest nHDLox values when compared with the elective cohort (median 1.35, IQR 0.97 to 1.85, P < 0.001). In multivariate analysis adjusted for age, sex, body mass index, and hypertension, nHDLox was a strong independent predictor of ACS (P < 0.001) but not of CAD (P > 0.05).CONCLUSION. HDL antioxidant function is reduced in patients with CAD. nHDLox is strongly associated with ACS. TRIAL REGISTRATION. German Clinical Trials Register DRKS00014037. FUNDING. Brandenburg Medical School Theodor Fontane, the BIOX Stiftung, and NIH grants R01AG059501 and R03AG059462. BACKGROUND. High-density lipoprotein (HDL) function rather than its concentration plays an important role in the pathogenesis of coronary artery disease (CAD). The aim of the present study was to determine whether reduced antioxidant function of HDL is associated with the presence of a stable CAD or acute coronary syndrome (ACS).METHODS. HDL function was measured in 2 cohorts: 1225 patients admitted electively for coronary angiography and 196 patients with ACS. A validated cell-free biochemical assay was used to determine reduced HDL antioxidant function, as assessed by increased HDL-lipid peroxide content (HDLox), which was normalized by HDL-C levels and the mean value of a pooled serum control from healthy participants (nHDLox; unitless). Results are expressed as median with interquartile range (IQR).
Authors
Benjamin Sasko, Linda Scharow, Rhea Mueller, Monique Jaensch, Werner Dammermann, Felix S. Seibert, Philipp Hillmeister, Ivo Buschmann, Martin Christ, Oliver Ritter, Nazha Hamdani, Christian Ukena, Timm H. Westhoff, Theodoros Kelesidis, Nikolaos Pagonas
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.180943.
Abstract
BACKGROUND. Alterations in circulating metabolites have been described in obese metabolic dysfunction-associated steatotic liver disease (MASLD), but data on lean MASLD are lacking. We investigated serum metabolites, including microbial bile acids (BAs) and short-chain fatty acids (SCFAs), and their association with lean and obese MASLD. METHODS. Serum samples from 204 subjects of European descent were allocated to four groups: lean healthy (n=61), lean MASLD (n=49), obese healthy (n=47) and obese MASLD (n=47). LC/MS-based metabolomics was performed followed by linear model analysis. MASLD prediction was assessed based on LASSO regression. Functional effects of significantly altered molecules were confirmed in organotypic 3D primary human liver cultures. RESULTS. Lean MASLD was characterized by elevated isobutyrate, along with higher methionine sulfoxide, propionate and phosphatidylcholines. Patients with obese MASLD had increased sarcosine and decreased lysine and asymmetric dimethylarginine. Using metabolites, sex and body mass index, MASLD vs. healthy could be predicted with a median AUC of 86.5% and 85.6% in the lean and obese subgroups, respectively. Functional experiments in organotypic 3D primary human liver cultures showed that propionate and isobutyrate induced lipid accumulation and altered expression of genes involved in lipid and glucose metabolism. CONCLUSION. Our results indicate that lean MASLD is characterized by a distinct metabolite pattern related to amino acid metabolism, lipids and SCFAs, while metabolic pathways of lipid accumulation are differentially activated by microbial metabolites. Our findings highlight an important role of microbial metabolites in MASLD pathogenesis, with implications for the predictive and mechanistic assessment of liver disease across different weight categories. FUNDING. The work received funding from the Robert Bosch Stiftung, Stuttgart, Germany, the Swedish Research Council [grant numbers 2021-02801, 2023-03015 and 2024-03401], the ERC Consolidator Grant 3DMASH [101170408], Ruth and Richard Julin Foundation for Gastroenterology [grant number 2021-00158], the SciLifeLab and Wallenberg National Program for Data-Driven Life Science [WASPDDLS22:006], and the Novo Nordisk Foundation [NNF23OC0085944 and NNF23OC0084420]. JT was supported by PMU-FFF [grant number E-18/28/148-FEL].
Authors
Mathias Haag, Stefan Winter, Aurino M. Kemas, Julia Tevini, Alexandra Feldman, Sebastian K. Eder, Thomas K. Felder, Christian Datz, Bernhard Paulweber, Gerhard Liebisch, Oliver Burk, Volker M. Lauschke, Elmar Aigner, Matthias Schwab
Abstract
Many risk-eligible women refuse tamoxifen for primary prevention of breast cancer due to concerns about common side effects such as vasomotor symptoms. Tamoxifen may also induce or worsen insulin resistance and hypertriglyceridemia, especially in women with obesity. Bazedoxifene/conjugated estrogens (BZA/CE) reduces vasomotor symptoms and is currently undergoing evaluation for breast cancer risk reduction. However, the impact of BZA/CE on insulin resistance and metabolic health, particularly in those with excess adiposity, is understudied. Here, we examined the effects of obesity on response to BZA/CE in a rat model of breast cancer risk using older ovary-intact rats. Female Wistar rats received carcinogen to increase mammary cancer risk and were fed a high-fat diet to promote obesity. Lean and obese rats were selected based on adiposity, then randomized to BZA/CE or vehicle for 8 weeks. BZA/CE reduced adiposity, enriched small (insulin-sensitive) mammary adipocytes, increased the abundance of beneficial metabolic gut microbes (Faecalbaculum rodentium and Odoribacter laneus), and reversed obesity-associated changes in lipids and adipokines. BZA/CE also reversed obesity-induced mammary enrichment of cell proliferation pathways, consistent with risk-reducing effects. Together, these data support the use of BZA/CE to improve metabolic health and reduce breast cancer risk in individuals with obesity.
Authors
Erin D. Giles, Katherine L. Cook, Ramsey M. Jenschke, Karen A. Corleto, Danilo Landrock, Tara N. Mahmood, Katherine E. Sanchez, Alina Levin, Stephen D. Hursting, Bruce F. Kimler, Barry S. Komm, Carol J. Fabian
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.174600.
Abstract
This study aimed to explore the potential correlation between the metabolic intermediate L-2-hydroxyglutarate (L-2-HG) and T cell exhaustion, as well as the underlying mechanisms involved. In this study, we investigated the presence of exhausted T cells (Tex) in patients under certain conditions: HIV infection, chronic leukemia, and hepatocellular carcinoma. To gain insights into the epigenetic signatures and transcriptome alterations in Tex, we employed a combination of RNA-seq and ATAC-seq analyses. To evaluate the impact of L-2-HG on mitochondrial function, differentiation, and anti-tumor capacity of Tex, we utilized in vitro cell culture experiments and animal tumor models. We observed mitochondrial depolarization and metabolic dysfunction in Tex, accompanied by a significant reduction in the metabolic intermediate L-2-HG level. Moreover, altered epigenetic characteristics was observed in Tex, including a substantial increase in H3K27me3 abundance. Culturing Tex with L-2-HG demonstrated improved mitochondrial metabolism, reduced H3K27me3 abundance, and enhanced memory T cell differentiation. In the mouse melanoma tumor model, L-2-HG-treated CD8+T cells for adoptive therapy led to significantly reduced tumor volume and significantly enhanced effector function of T cells. The study revealed L-2-HG acted as an immune metabolite through epigenetic modifications of Tex.
Authors
Yanying Yang, Xiaoyan Li, Fangming Liu, Mingyue Ma, Ying Yang, Chengchao Ruan, Yan Lu, Xiaoyang Li, Xiangdong Wang, Yinghong Shi, Zheng Zhang, Hua Wang, Zhouli Cheng, Duojiao Wu
Abstract
Leber hereditary optic neuropathy (LHON) is a paradigm for mitochondrial retinopathy due to mitochondrial DNA (mtDNA) mutations. However, the mechanism underlying retinal cell-specific effects of LHON-linked mtDNA mutations remains poorly understood and there has been no effective treatment or cure for this disorder. Using a mice model bearing a LHON-linked ND6P25L mutation, we demonstrated that the mutation caused retinal cell-specific deficiencies, especially in retinal ganglion cells (RGC), rods and Müller cells. Single-cell RNA sequencing revealed cell-specific dysregulation of oxidative phosphorylation and visual signaling pathways in the mutant retina. Strikingly, ND6 mutation-induced dysfunctions caused abnormal vitamin A (VA) metabolism essential for visual function. VA supplementation remarkably alleviated retinal deficiencies, including reduced fundus lesion and retinal thickness, and increasing numbers of RGCs, photoreceptors and Müller cell neurites. The restoration of visual functions with VA treatment were further evidenced by correcting dysregulations of phototransduction cascade and neurotransmitter transmission and restoring electrophysiological properties. Interestingly, VA supplementation markedly rescued the abnormal mitochondrial morphologies and functions in the mutant retina. These findings provide new insight into retina-specific pathophysiology of mitochondrial retinopathy arising from vitamin A deficiency and mitochondrial dysfunction induced by mtDNA mutation and step toward for therapeutic intervention for LHON and other mitochondrial retinopathy.
Authors
Cheng Ai, Huiying Li, Chunyan Wang, Yanchun Ji, Douglas C. Wallace, Junbin Qian, Yimin Zhu, Min-Xin Guan
Citation Information: JCI Insight. 2025. https://doi.org/10.1172/jci.insight.190105.
Abstract
The use of genetically engineered tools, including combinations of Cre-LoxP and Flp-FRT systems, enable the interrogation of complex biology. Steroidogenic factor-1 (SF-1) is expressed in the ventromedial hypothalamic nucleus (VMH). Development of genetic tools, such as mice expressing Flp recombinase (Flp) in SF-1 neurons (Sf-1-Flp), will be useful for future studies that unravel the complex physiology regulated by the VMH. Here, we developed and characterized Sf-1-Flp mice and demonstrated its utility. Flp sequence was inserted into Sf-1 locus with P2A. This insertion did not affect Sf-1 mRNA expression levels and Sf-1-Flp mice do not have any visible phenotypes. They are fertile and metabolically comparable to wild-type littermate mice. Optogenetic stimulation using adeno-associated virus (AAV)-bearing Flp-dependent channelrhodopsin-2 (ChR2) increased blood glucose and skeletal muscle PGC-1α in Sf-1-Flp mice. This was similar to SF-1 neuronal activation using Sf-1-BAC-Cre and AAV-bearing Cre-dependent ChR2. Finally, we generated Sf-1-Flp mice that lack β2-adrenergic receptors (Adrβ2) only in skeletal muscle with a combination of Cre/LoxP technology (Sf-1-Flp::SKM∆Adrβ2). Optogenetic stimulation of SF-1 neurons failed to increase skeletal muscle PGC-1α in Sf-1-Flp::SKM∆Adrβ2 mice, suggesting that Adrβ2 in skeletal muscle is required for augmented skeletal muscle PGC-1α by SF-1 neuronal activation. Our data demonstrate that Sf-1-Flp mice are useful for interrogating complex physiology.
Authors
Marco Galvan, Mina Fujitani, Samuel R. Heaselgrave, Shreya Thomas, Bandy Chen, Jenny J. Lee, Steven C. Wyler, Joel K. Elmquist, Teppei Fujikawa
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