Metabolism
Abstract
Hepatocyte senescence is increasingly recognized as a pathogenic driver of metabolic dysfunction–associated steatohepatitis (MASH). Through single-nucleus transcriptomic profiling, we identified a discrete population of disease-associated hepatocytes (daHep) exhibiting enrichment for senescence markers in MASH livers. The emergence of senescent hepatocytes was associated with a marked induction of hepatic thymocyte selection associated (THEMIS) expression in both murine and human MASH. Genetic ablation of Themis, either globally or specifically in hepatocytes, resulted in significant expansion of daHep and senescent hepatocyte populations and exacerbated MASH pathology in mice. Single-nucleus transcriptomic analysis revealed a central role for THEMIS in shaping the cellular landscape of both parenchymal and nonparenchymal compartments within the MASH liver microenvironment. Conversely, adeno-associated virus–mediated overexpression of THEMIS suppressed hepatocyte senescence and attenuated diet-induced MASH. Mechanistic studies revealed that THEMIS deficiency promoted aberrant ERK phosphorylation and hepatocyte senescence. These findings establish THEMIS as a critical hepatoprotective factor that restrains hepatocyte senescence and mitigates metabolic liver disease progression.
Authors
Xiaoxue Qiu, You Lu, Yuwei Tang, Linkang Zhou, Yu-tung Lee, Ziyi Meng, Zhimin Chen, Fnu Pradeepa, Lanuza A.P. Faccioli, Zhiping Hu, Alejandro Soto-Gutierrez, Siming Li, Jiandie D. Lin
Abstract
Iron overload has emerged as a significant risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), a growing global health concern. Despite this association, the precise mechanisms by which hepatic iron and its regulatory genes connect liver pathology to systemic metabolic dysfunction remain elusive. Here, we demonstrate that humoral signals originating from iron-overloaded hepatocytes act as critical mediators driving systemic metabolic dysfunction in MASLD. Ferroportin (FPN, SLC40A1), the sole cellular iron exporter, exhibits markedly reduced expression in hepatocytes of both human patients and mouse models with MASLD, concomitant with hepatic iron accumulation. Functionally, hepatocyte-specific FPN deletion significantly exacerbates diet-induced obesity and insulin resistance, with these metabolic perturbations accompanied by decreased energy expenditure and impaired thermogenic capacity. Mechanistically, we establish that hepatic iron accumulation resulting from FPN deficiency enhances the production of two specific hepatokines, Fetuin-A and LECT2, through activation of the transcription factor FoxO1. Notably, therapeutic interventions — including genetic silencing of these hepatokines, hepatocyte-specific FPN overexpression, or oral iron chelation — effectively reverse the metabolic dysfunction phenotypes. These findings provide critical insights into the pathophysiological mechanisms linking MASLD to systemic metabolic disorders and highlight promising therapeutic strategies to combat these diseases.
Authors
Hye Jin Jo, Ayoung Kim, Hyunsoo Rho, Ae Kyung Park, Gil-Hwan Kim, Seo Jeong Jo, Hao Yuxin, You-Jung Hong, Ji Min Yeon, Hwang Chan Yu, Mi-Young Song, Jeongwoo Park, Yeon Hee Jeong, Sung Eun Hong, Hyo Jin Yeon, Da Young Oh, Philipp E. Scherer, Cheol Soo Choi, Dong Hyeon Lee, Sung Hwan Ki, Keon Wook Kang, Murim Choi, Byung-Hyun Park, Eun Ju Bae, Sang Geon Kim, Won Kim, Chang Yeob Han
Abstract
The liver plays a critical role in lipid homeostasis, where lipids are either secreted as very-low-density lipoproteins (VLDL) or stored in lipid droplets (LDs). However, the regulatory mechanisms governing these two interconnected processes remain poorly understood. Here, we demonstrate that SEC16B functions as a lipid-responsive regulator in the liver, promoting VLDL secretion and LD expansion to handle lipid flux and maintain lipid homeostasis. Genome-wide association studies have identified single-nucleotide polymorphisms in SEC16B to be highly associated with serum lipid levels in humans. Hepatic Sec16b deficiency decreases serum lipid levels by impairing VLDL secretion through mechanisms that are at least partially independent of microsomal triglyceride transfer protein (MTP)-mediated ApoB lipidation and COPII-mediated intracellular trafficking. SEC16B partially localizes at ER-LD contact sites and promotes LD expansion by facilitating the targeting of ER proteins to LDs. More importantly, suppression of Sec16b dramatically lowers serum lipid levels and reduces atherosclerotic lesion size in Ldlr null mice. These data reveal a mechanism that coordinates VLDL and LD metabolism and suggest SEC16B as a potential therapeutic target for atherosclerosis treatment.
Authors
Wei Lu, Zhiming Zhao, Donald Molina, Huaxun Fan, Ruicheng Shi, Ye Tian, Raja Gopoju, Tiantian Yang, Xinyuan Zhang, Yanqiao Zhang, Kai Zhang, Jaume Amengual, Bo Wang
Abstract
Sphingosine-1-phosphate lyase (SPL) insufficiency syndrome (SPLIS) or nephrotic syndrome type 14 (NPHS14), is an autosomal recessive multisystem disorder caused by loss-of-function mutations in SGPL1, encoding the enzyme responsible for the terminal degradation of sphingosine-1-phosphate (S1P). We investigated a patient carrying a previously undescribed c.1084T>A (p.Ser362Thr) SGPL1 variant and analyzed the metabolic and cellular consequences of SPL deficiency using patient fibroblasts, SGPL1-knockout HEK293T cells, and Sgpl1–/– and Sgpl1rosa+fl/fl mice. Metabolic stable isotope labelling revealed that SPL deficiency does not invariably result in S1P accumulation. Instead, SPL-deficient cells maintain near-normal S1P levels through (i) feedback regulation of de novo sphingolipid synthesis via the ORMDL–ceramide axis and (ii) increased diversion of excess ceramides into glycosphingolipids. However, perturbation of sphingolipid homeostasis — either by exogenous sphingolipid load or disruption of compensatory regulation — induces pathological intracellular S1P accumulation. In vivo, Sgpl1–/– mice exhibited pronounced urinary S1P excretion and renal S1P enrichment, accompanied by cytoskeletal disorganization and impaired epithelial morphogenesis. Mechanistically, we identify aberrant Rho–ROCK signaling as a key mediator of S1P-driven cytoskeletal dysregulation. Pharmacological ROCK inhibition with Fasudil mitigated renal cytoskeletal defects in Sgpl1–/– and Sgpl1rosa+fl/fl mice and partially restored epithelial architecture. These findings redefine the metabolic consequences of SPL deficiency and identify S1P-driven Rho–ROCK hyperactivation as a tractable therapeutic target in SPLIS.
Authors
Adam Majcher, Ranjha Khan, Kathrin Buder, Florence Bourquin, Julie D. Saba, Thorsten Hornemann
Abstract
Apolipoprotein B (APOB) containing lipoproteins contribute to atherosclerosis by entering the arterial wall through the endothelial cell (EC) surface receptors scavenger receptor-BI (SR-BI) and activin receptor-like kinase 1 (ALK1). We used N-terminal fragments of APOB, molecular modeling, and site-directed mutagenesis to identify and block the binding of chylomicrons and LDL to these receptors in cells and mice. We discovered that different APOB regions interact with SR-BI and ALK1 expressed on ECs APOB48 lipoproteins were only internalized by SR-BI. A fragment of APOB, comprising 18% of the N-terminal sequence, APOB18, reduced the uptake and transport of both chylomicrons and LDL by ECs, whereas a shorter fragment, APOB12, only blocked ALK1 mediated uptake of APOB100 containing lipoproteins. Importantly, overexpressing APOB18 decreased atherosclerosis in hypercholesterolemic mice. These findings identify the N-terminal region of APOB as the cause of atherosclerosis and illustrate an approach to treating or preventing vascular disease.
Authors
Ainara G. Cabodevilla, Camila Calistru, Waqas Younis, Dimitris Nasias, Tse W.W. Ho, Narasimha Anaganti, Swati Valmiki, Sujith Rajan, Jana Gjini, Rufina Kore, Carmen Hannemann, Nicholas O. Davidson, Tomas Vaisar, Jenny E. Kanter, Karin E. Bornfeldt, Edward A. Fisher, Warren L. Lee, Tobias Madl, M. Mahmood Hussain, Ira J. Goldberg
Abstract
Complete response is rarely observed in lung cancer molecular targeted therapy, despite great clinical success. Here, we found that molecular therapy targeted toward EGFR mutant, KRAS mutant, or ALK fusion lung cancer induced cholesterol biosynthesis, which promoted cancer cells to enter dormancy and thus escape drug killing. Combined statin treatments effectively blocked cholesterol biosynthesis, prevented cancer cells from entering dormancy, and thus resulted in dramatic tumor regression. We further identified a subpopulation of cycling cancer cells that persisted during molecular targeted therapy and remained sensitive to aurora kinase inhibitors. Triple-targeting cholesterol biosynthesis, aurora kinase, and individual oncogenic drivers almost eradicated all the cancer cells. Therapy-induced cancer dormancy was mainly attributed to activation of unfolded protein response, specifically the PERK-eIF2α axis, which triggers cholesterol biosynthesis and AKT signaling. Collectively, this work uncovers an unexpected role of a therapy-induced prosurvival program in promoting cancer dormancy and provides a potentially effective strategy to prevent drug resistance.
Authors
Yikai Zhao, Yijia Zhou, Linnuo Pan, Geng G. Tian, Hsin-Yi Huang, Shijie Tang, Ming Lu, Zhangsen Zhou, Peng Zhang, Luonan Chen, Lele Zhang, Liang Hu, Hongbin Ji
Abstract
Glutathione (GSH) maintains a reduced cellular environment and is widely believed to mitigate disease-associated oxidative damage to proteins, thereby protecting against metabolic dysfunction–associated steatotic liver disease (MASLD). However, this widely accepted assumption remains largely untested because of challenges in physiologically manipulating hepatic GSH levels during disease development. Here, we have utilized liver-specific overexpression of cation transport regulator homolog 1 (Chac1), a recently identified intracellular GSH-degrading enzyme, to induce hepatic GSH depletion during MASLD progression. Contrary to canonical doctrine, GSH depletion unexpectedly protects against MASLD by substantially decreasing hepatic lipogenesis and fibrosis without triggering an oxidative stress response. Mechanistically, GSH depletion does not cause global protein oxidation but instead selectively oxidizes and destabilizes fatty acid synthase while decreasing lipogenic gene expression at the transcriptional level, collectively suppressing lipogenesis. Interestingly, Chac1 expression is decreased in livers of patients with MASLD, highlighting its potential therapeutic relevance. These findings revise the conventional view of GSH in protein redox and demonstrate that targeted redox manipulation through GSH depletion protects against MASLD.
Authors
Xiang-Yu Liu, Guoxiao Wang, Yingying Yu, Haopeng Xiao, Kentaro Oh-hashi, Xu Shi, Shuning Zheng, Robert Gerszten, C. Ronald Kahn
Abstract
Thyroid hormones (THs [T3 and T4] ) are key regulators of metabolic rate and nutrient metabolism. They are controlled centrally and peripherally in a coordinated manner to elegantly match T3-mediated energy expenditure (EE) with energy availability. Hypothyroidism reduces EE and has long been blamed for obesity; however, emerging evidence suggests that, instead, obesity may drive thyroid dysfunction. Thus, we used a mouse model of diet-induced obesity to determine its direct effects on thyroid histopathology and function, deiodinase activity, and T3 action. Strikingly, overnutrition induced hypothyroidism within 3 weeks. Levels of thyroidal THs and their precursor protein thyroglobulin decreased, and ER stress was induced, indicating that thyroid function was directly impaired. We also observed pronounced histological and vascular expansion in the thyroid. Overnutrition additionally suppressed T4 activation, rendering the mice resistant to T4 and reducing EE. Our findings collectively show that overnutrition deals a double strike to TH biosynthesis and action, despite large efforts to adapt — but, fortunately, thyroid dysfunction in mice can be reversed by weight loss. In humans, BMI correlated with thyroidal vascularization, importantly demonstrating preliminary translatability. These studies lay the groundwork for obesity therapies that tackle hypothyroidism, which are much needed, as no current obesity treatment works for everyone.
Authors
Jessica Rampy, Alejandra Paola Torres-Manzo, Kendra Hoffsmith, Matthew A. Loberg, Quanhu Sheng, Federico Salas-Lucia, Antonio C. Bianco, Rafael Arrojo e Drigo, Huiying Wang, Vivian L. Weiss, Nancy Carrasco
Abstract
The lymphatic system plays a central role in lipid absorption by transporting triglyceride-rich particles called chylomicrons (CMs) from the small intestine to the systemic circulation. However, the molecular mechanism by which CMs get into the intestinal lymphatics is unknown. Here we demonstrated that GPR182, an atypical chemokine receptor in lymphatic endothelial cells, mediates dietary fat absorption. GPR182 knockout mice exhibit a selective increase in circulating high-density lipoproteins and are resistant to dietary-induced obesity. GPR182 ablation in mice leads to poor lipid absorption and thereby a delay in growth during development. GPR182 broadly interacts with and transports lipoproteins. Transmission electron microscopy analysis reveals that mechanistically, loss of GPR182 prevents CMs from entering the lacteal lumen of the small intestine. Consistent with this, GPR182 blockade with monoclonal antibodies protects mice from diet- induced obesity and treats existing obesity. Together, our study identifies GPR182 as a lipoprotein receptor that mediates dietary fat absorption and supports GPR182 blockade as a feasible approach to treat obesity and related disorders.
Authors
Zhiwei Sun, Robert J. Torphy, Emily N. Miller, Anza Darehshouri, Isaac Vigil, Taichi Terai, Eck Eleanor, Yi Sun, Yujie Guo, Dustin P. Fykstra, Elliott J. Yee, Junyi Hu, Ross M. Kedl, Erika L. Lasda, Jay R. Hesselberth, Julie A. Siegenthaler, Paul S. MacLean, Kimberley D. Bruce, Gwendalyn J. Randolph, Richard D. Schulick, Yuwen Zhu
Abstract
Gemcitabine-based chemotherapy is the standard treatment regime for advanced intrahepatic cholangiocarcinoma (iCCA), but the frequent presence of chemoresistance limits its efficacy. Here, we identified isocitrate dehydrogenase 1 (IDH1) as the crucial target that confers chemoresistance of iCCA to gemcitabine using a druggable CRISPR/Cas9 library. The positive association between IDH1 expression and chemoresistance was revealed in a gemcitabine-treated iCCA cohort and cell-based drug sensitivity assays. Utilizing patient-derived organoids, cell line-derived xenografts, and patient-derived xenografts, we demonstrated that IDH1 knockdown or IDH1 pharmacological inhibition facilitated gemcitabine efficacy in these pre-clinical iCCA models carrying wild-type IDH1 (wtIDH1). Mechanistically, wtIDH1 oxidizes isocitrate to generate α-ketoglutarate and NADPH, thereby coping with the oxidative stress induced by gemcitabine, maintaining cellular redox homeostasis, and ultimately leading to their chemoresistance to gemcitabine. Significantly, ivosidenib, the FDA-approved allosteric IDH1 inhibitor, demonstrated synergistic anti-tumor efficacy with gemcitabine in wtIDH1 pre-clinical iCCA models through boosting intracellular oxidative stress under physiological conditions. The low level of Mg2+, an ion that competitively hinders binding of ivosidenib on wtIDH1, in iCCA tumor microenvironment contributed to the expanded therapeutic window of ivosidenib in patients with iCCA. Our work revealed the potency of combining targeting IDH1 and chemotherapy against wtIDH1 iCCA and other tumors.
Authors
Xiuxian Li, Zhixiao Song, Shusheng Lin, Man Luo, Shaoru Liu, Yang Liu, Fapeng Zhang, Leibo Xu, Chao Liu, Honghua Zhang
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)