Multiomics analyses decipher intricate changes in the cellular and metabolic landscape of steatotic livers upon dietary restriction and sleeve gastrectomy DOI Creative Commons
Shuai Chen, Qinghe Zeng, Xiurong Cai

et al.

International Journal of Biological Sciences, Journal Year: 2024, Volume and Issue: 20(11), P. 4438 - 4457

Published: Jan. 1, 2024

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic, progressive that encompasses spectrum of steatosis, steatohepatitis (or MASH), and fibrosis. Evidence suggests dietary restriction (DR) sleeve gastrectomy (SG) can lead to remission hepatic steatosis inflammation through weight loss, but it unclear whether these procedures induce distinct metabolic or immunological changes in MASLD livers. This study aims elucidate the intricate following DR, SG sham surgery rats fed high-fat diet as model obesity-related MASLD, comparison clinical cohort patients undergoing SG. Single-cell single-nuclei transcriptome analysis, spatial metabolomics, immunohistochemistry revealed landscape, while circulating biomarkers were measured serum samples. Artificial intelligence (AI)-assisted image analysis characterized distribution hepatocytes, myeloid cells lymphocytes. In experimental rats, improved body mass index, injury triglyceride levels. Both DR attenuated fibrosis rats. Metabolism-related genes (

Language: Английский

Spatial single-cell mass spectrometry defines zonation of the hepatocyte proteome DOI Creative Commons
Florian A. Rosenberger, Marvin Thielert, Maximilian T. Strauss

et al.

Nature Methods, Journal Year: 2023, Volume and Issue: 20(10), P. 1530 - 1536

Published: Oct. 1, 2023

Single-cell proteomics by mass spectrometry is emerging as a powerful and unbiased method for the characterization of biological heterogeneity. So far, it has been limited to cultured cells, whereas an expansion complex tissues would greatly enhance insights. Here we describe single-cell Deep Visual Proteomics (scDVP), technology that integrates high-content imaging, laser microdissection multiplexed spectrometry. scDVP resolves context-dependent, spatial proteome murine hepatocytes at current depth 1,700 proteins from cell slice. Half was differentially regulated in manner, with protein levels changing dramatically proximity central vein. We applied machine learning classes images, which subsequently inferred imaging data alone. applicable healthy diseased complements other omics technologies.

Language: Английский

Citations

88
Hepatic stellate cells regulate liver fatty acid utilization via plasmalemma vesicle-associated protein DOI Creative Commons
Daniel Hansen,

Jon T. Jensen,

Christen Lykkegaard Andersen

et al.

Cell Metabolism, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

The liver is essential for normal fatty acid utilization during fasting. Circulating acids are taken up by hepatocytes and esterified as triacylglycerols either oxidative metabolization ketogenesis or export. Whereas the regulation of oxidation in well understood, uptake retention non-esterified not. Here, we show that murine hepatic stellate cells (HSCs) their abundantly expressed plasmalemma vesicle-associated protein (PLVAP) control substrate preference fasting energy metabolism. HSC-specific ablation PLVAP mice elevated insulin signaling improved glucose tolerance. Fasted HSC knockout showed suppressed esterification into di- triacylglycerols, shifting metabolism from to reliance on carbohydrates. By super-resolution microscopy, localized caveolae residing along sinusoidal lumen, supporting a role HSCs PLVAP-diaphragmed liver.

Language: Английский

Citations

3
Spatial mapping of hepatic ER and mitochondria architecture reveals zonated remodeling in fasting and obesity DOI Creative Commons
Güneş Parlakgül, Song Pang, Leonardo Luís Artico

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: May 10, 2024

The hepatocytes within the liver present an immense capacity to adapt changes in nutrient availability. Here, by using high resolution volume electron microscopy, we map how hepatic subcellular spatial organization is regulated during nutritional fluctuations and as a function of zonation. We identify that fasting leads remodeling endoplasmic reticulum (ER) architecture hepatocytes, characterized induction single rough ER sheet around mitochondria, which becomes larger flatter. These alterations are enriched periportal mid-lobular but not pericentral hepatocytes. Gain- loss-of-function vivo models demonstrate Ribosome receptor binding protein1 (RRBP1) required enable fasting-induced sheet-mitochondria interactions regulate fatty acid oxidation. Endogenous RRBP1 regions liver. In obesity, ER-mitochondria distinct fails induce sheet-mitochondrion interactions. findings illustrate importance molecular for hepatocyte metabolic flexibility.

Language: Английский

Citations

14
Beyond fission and fusion—Diving into the mysteries of mitochondrial shape DOI Creative Commons

Noga Preminger,

Maya Schuldiner

PLoS Biology, Journal Year: 2024, Volume and Issue: 22(7), P. e3002671 - e3002671

Published: July 1, 2024

Mitochondrial shape and network formation have been primarily associated with the well-established processes of fission fusion. However, recent research has unveiled an intricate multifaceted landscape mitochondrial morphology that extends far beyond conventional fission–fusion paradigm. These less-explored dimensions harbor numerous unresolved mysteries. This review navigates through diverse influencing formation, highlighting intriguing complexities gaps in our understanding architecture. The exploration encompasses various scales, from biophysical principles governing membrane dynamics to molecular machineries shaping mitochondria, presenting a roadmap for future this evolving field.

Language: Английский

Citations

9
Ketogenesis supports hepatic polyunsaturated fatty acid homeostasis via fatty acid elongation DOI Creative Commons
Eric D. Queathem, Zahra Moazzami, David B. Stagg

et al.

Science Advances, Journal Year: 2025, Volume and Issue: 11(5)

Published: Jan. 29, 2025

Ketogenesis is a dynamic metabolic conduit supporting hepatic fat oxidation particularly when carbohydrates are in short supply. Ketone bodies may be recycled into anabolic substrates, but physiological role for this process has not been identified. Here, we use mass spectrometry–based 13 C-isotope tracing and shotgun lipidomics to establish link between ketogenesis lipid anabolism. Unexpectedly, mouse liver primary hepatocytes consumed ketone support fatty acid biosynthesis via both de novo lipogenesis (DNL) polyunsaturated (PUFA) elongation. While an acetoacetate intermediate was absolutely required source DNL, PUFA elongation activation of by cytosolic acetoacetyl–coenzyme A synthetase (AACS). Moreover, AACS deficiency diminished free esterified PUFAs hepatocytes, while ketogenic insufficiency depleted increased triacylglycerols. These findings suggest that influences metabolism, representing molecular mechanism through which could influence systemic physiology chronic diseases.

Language: Английский

Citations

1
Mitochondrial alterations and signatures in hepatocellular carcinoma DOI Creative Commons
Tsung‐Hsien Chen, Shu-Hsien Lin, Ming‐Yang Lee

et al.

Cancer and Metastasis Reviews, Journal Year: 2025, Volume and Issue: 44(1)

Published: Feb. 18, 2025

Language: Английский

Citations

1
Efficient cell-wide mapping of mitochondria in electron microscopic volumes using webKnossos DOI Creative Commons
Yi Jiang, H. Wang, Kevin M. Boergens

et al.

Cell Reports Methods, Journal Year: 2025, Volume and Issue: 5(2), P. 100989 - 100989

Published: Feb. 1, 2025

Language: Английский

Citations

1
Multi-zonal liver organoids from human pluripotent stem cells DOI
Hasan Al Reza,

Connie Santangelo,

Kentaro Iwasawa

et al.

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: April 16, 2025

Language: Английский

Citations

1
Food perception induces fast fragmentation of hepatic mitochondria DOI
Arnaud Chevrollier, Jérôme Boursier, Valérie Desquiret‐Dumas

et al.

Trends in Endocrinology and Metabolism, Journal Year: 2024, Volume and Issue: 35(8), P. 680 - 682

Published: June 18, 2024

Language: Английский

Citations

3
Mitochondrial fusion and cristae reorganization facilitate acquisition of cardiomyocyte identity during reprogramming of murine fibroblasts DOI Creative Commons
Brian Spurlock, Yifang Xie, Yiran Song

et al.

Cell Reports, Journal Year: 2025, Volume and Issue: 44(3), P. 115377 - 115377

Published: March 1, 2025

Cardiomyocytes (CMs) rely on mitochondrial energy produced in highly interconnected networks. Direct reprogramming of cardiac fibroblasts (CFs) into induced CMs (iCMs) shows promise for treating injury, but little work has investigated energetics and morphology during the conversion CFs to iCMs. We characterized mitochondria direct murine neonatal (mnCFs). Reprogramming increased respiration interconnectivity not levels native CMs. therefore whether perturbations dynamics impacted reprogramming. Mitochondrial fusion (joining) was essential iCM generation, while various fission (dividing) genes were barriers. In particular, loss regulator 1 like (Mtfr1l) significantly yield functionally mature iCMs respiration. These changes countered by concomitant effector optical atrophy protein (Opa1). The present study advances our understanding barriers mechanisms

Language: Английский

Citations

0