Regulation of liver subcellular architecture controls metabolic homeostasis

Parlakgül, Güneş; Arruda, Ana Paula; Pang, Song; Cagampan, Erika; Min, Nina; Güney, Ekin; Lee, Grace Yankun; Inouye, Karen; Hess, Harald F.; Xu, Chengpei; Hotamışlıgil, Gökhan S.

doi:10.1038/s41586-022-04488-5

Cited by 74 publications

(94 citation statements)

References 28 publications

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“…Change of the endoplasmic reticulum, involved in the creation and shaping of proteins, is one of the modifications occurring during MAFLD pathogenesis [ 11 ] with subsequent modification of the hepatic transcriptome, proteome, and secretome [ 12 , 13 ]. Among the proteins in which hepatic production is increased with MAFLD, attention has been given to fetuin-A [ 14 ], a hepatocyte secreted glycoprotein presented as a hepatokine [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Fetuin-A in Activated Liver Macrophages Is a Key Feature of Non-Alcoholic Steatohepatitis

et al. 2022

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Fetuin-A, a plasma multifunctional protein known to play a role in insulin resistance, is usually presented as a liver secreted protein. However, fetuin-A adipose tissue production has been also described. Here, we evaluated fetuin-A production by the liver and the adipose tissue during metabolic dysfunction-associated fatty liver disease (MAFLD)-non-alcoholic steatohepatitis (NASH) development. Fetuin-A was evaluated by enzyme-linked immunosorbent assay (ELISA), polymerase chain reaction (PCR), Western blot, and immunofluorescence in male foz−/− mice fed a normal diet (ND) or a high fat diet (HFD) at various timepoints and in MAFLD-NASH patients. Foz−/− mice fed a short-term HFD developed liver steatosis, insulin resistance, and increased circulating levels of fetuin-A compared to ND-fed mice. In mice and patients with NASH, fetuin-A was located not only in healthy or steatotic hepatocytes but also in some macrophages forming lipogranulomas. In both mice and humans, a significant amount of fetuin-A was present in the adipose tissue compared to the liver. However, messenger ribonucleic acid levels and cell culture experiments indicate that fetuin-A is produced by the liver but not by the adipose tissue. In conclusion, fetuin-A is produced by steatotic hepatocytes at early timepoints in MAFLD and correlates with insulin resistance both in mice and humans. In NASH, fetuin-A also co-localizes with activated liver macrophages and could be interpreted as a signal released by damaged hepatocytes.

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Section: Introductionmentioning

confidence: 99%

Fetuin-A in Activated Liver Macrophages Is a Key Feature of Non-Alcoholic Steatohepatitis

et al. 2022

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“…Some studies feature reconstructions of single‐cell organisms and small organisms such as the budding yeast ( S. cerevisiae ), 47 parasite Trypanosoma brucei 48 or the ringed worm ( P. dumerilii ) at 6 days post‐fertilisation 49 . Some of the larger samples are intersegmental vessels and dorsal‐lateral lanastomotic vessels in zebrafish embyos 50 (FIB‐SEM), root tips of the barrelclover ( M. truncatula ), 38 (SBF‐SEM), human and mouse fibrous connective tissue 51 (SBF‐SEM) and mouse liver tissue 52 (FIB‐SEM).…”

Section: Trends In Volume Electron Microscopymentioning

confidence: 99%

“…Volume EM studies with FIB‐SEM have resulted in high resolution 3D reconstructions including (but not limited to) HeLa cells, T cells and macrophages, 2,43,53 cancer cells, 54 mouse primary beta cells 3 and COS‐7 cells 55 . Moreover, studies have been performed on human cardiac telocytes, 56 mouse liver tissue 52 and lung alveolar epithelium 57 . Studies of abnormal ultrastructure are emerging, including breast carcinoma and pancreatic adenocarcinoma 46 …”

Section: Trends In Volume Electron Microscopymentioning

confidence: 99%

How innovations in methodology offer new prospects for volume electron microscopy

Kievits

Lane

Carroll

et al. 2022

Journal of Microscopy

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Detailed knowledge of biological structure has been key in understanding biology at several levels of organisation, from organs to cells and proteins. Volume electron microscopy (volume EM) provides high resolution 3D structural information about tissues on the nanometre scale. However, the throughput rate of conventional electron microscopes has limited the volume size and number of samples that can be imaged. Recent improvements in methodology are currently driving a revolution in volume EM, making possible the structural imaging of whole organs and small organisms. In turn, these recent developments in image acquisition have created or stressed bottlenecks in other parts of the pipeline, like sample preparation, image analysis and data management. While the progress in image analysis is stunning due to the advent of automatic segmentation and server-based annotation tools, several challenges remain. Here we discuss recent trends in volume EM, emerging methods for increasing throughput and implications for sample preparation, image analysis and data management.

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“…UPR activation is evident in obese animals and humans in several tissues, including the brain, liver, muscle, and adipose ( Sharma et al, 2008 ; Kawasaki et al, 2012 ; Horwath et al, 2017 ). Indeed, obesity causes a drastic disruption to and rearrangement of ER morphology in hepatocytes ( Parlakgül et al, 2022 ). However, it remains unclear how obesity leads to ER stress.…”

Section: The Endoplasmic Reticulum and Endoplasmic Reticulum Stressmentioning

confidence: 99%

Pathways Linking Nicotinamide Adenine Dinucleotide Phosphate Production to Endoplasmic Reticulum Protein Oxidation and Stress

Gansemer

Rutkowski

2022

Front. Mol. Biosci.

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The endoplasmic reticulum (ER) lumen is highly oxidizing compared to other subcellular compartments, and maintaining the appropriate levels of oxidizing and reducing equivalents is essential to ER function. Both protein oxidation itself and other essential ER processes, such as the degradation of misfolded proteins and the sequestration of cellular calcium, are tuned to the ER redox state. Simultaneously, nutrients are oxidized in the cytosol and mitochondria to power ATP generation, reductive biosynthesis, and defense against reactive oxygen species. These parallel needs for protein oxidation in the ER and nutrient oxidation in the cytosol and mitochondria raise the possibility that the two processes compete for electron acceptors, even though they occur in separate cellular compartments. A key molecule central to both processes is NADPH, which is produced by reduction of NADP+ during nutrient catabolism and which in turn drives the reduction of components such as glutathione and thioredoxin that influence the redox potential in the ER lumen. For this reason, NADPH might serve as a mediator linking metabolic activity to ER homeostasis and stress, and represent a novel form of mitochondria-to-ER communication. In this review, we discuss oxidative protein folding in the ER, NADPH generation by the major pathways that mediate it, and ER-localized systems that can link the two processes to connect ER function to metabolic activity.

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Regulation of liver subcellular architecture controls metabolic homeostasis

Cited by 74 publications

References 28 publications

Fetuin-A in Activated Liver Macrophages Is a Key Feature of Non-Alcoholic Steatohepatitis

Fetuin-A in Activated Liver Macrophages Is a Key Feature of Non-Alcoholic Steatohepatitis

How innovations in methodology offer new prospects for volume electron microscopy

Pathways Linking Nicotinamide Adenine Dinucleotide Phosphate Production to Endoplasmic Reticulum Protein Oxidation and Stress

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