Disorganization and degeneration of liver sympathetic innervations in nonalcoholic fatty liver disease revealed by 3D imaging.
TL;DR: In this article, the authors used 3D immunoimaging to explore the integrity of the hepatic nervous system in experimental and human nonalcoholic fatty liver disease (NAFLD) and demonstrate parallel signs of mild degeneration and axonal sprouting of sympathetic innervations in early stages of experimental NAFLD and a collapse of sympathetic arborization in steatohepatitis.
Abstract: Hepatic nerves have a complex role in synchronizing liver metabolism. Here, we used three-dimensional (3D) immunoimaging to explore the integrity of the hepatic nervous system in experimental and human nonalcoholic fatty liver disease (NAFLD). We demonstrate parallel signs of mild degeneration and axonal sprouting of sympathetic innervations in early stages of experimental NAFLD and a collapse of sympathetic arborization in steatohepatitis. Human fatty livers display a similar pattern of sympathetic nerve degeneration, correlating with the severity of NAFLD pathology. We show that chronic sympathetic hyperexcitation is a key factor in the axonal degeneration, here genetically phenocopied in mice deficient of the Rac-1 activator Vav3. In experimental steatohepatitis, 3D imaging reveals a severe portal vein contraction, spatially correlated with the extension of the remaining nerves around the portal vein, enlightening a potential intrahepatic neuronal mechanism of portal hypertension. These fundamental alterations in liver innervation and vasculature uncover previously unidentified neuronal components in NAFLD pathomechanisms.
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TL;DR: In this paper , the authors used volume immunostaining and optical clearing technology combined with light sheet fluorescence microscopy to investigate the LC cytoarchitecture and tau cytoskeletal pathology in relation to possible propagation patterns of disease-associated tau.
Abstract: Tau pathology of the noradrenergic locus coeruleus (LC) is a hallmark of several age-related neurodegenerative disorders, including Alzheimer's disease. However, a comprehensive neuropathological examination of the LC is difficult due to its small size and rod-like shape. To investigate the LC cytoarchitecture and tau cytoskeletal pathology in relation to possible propagation patterns of disease-associated tau in an unprecedented large-scale three-dimensional view, we utilized volume immunostaining and optical clearing technology combined with light sheet fluorescence microscopy. We examined AT8+ pathological tau in the LC/pericoerulear region of 20 brains from Braak neurofibrillary tangle (NFT) stage 0-6. We demonstrate an intriguing morphological complexity and heterogeneity of AT8+ cellular structures in the LC, representing various intracellular stages of NFT maturation and their diverse transition forms. We describe novel morphologies of neuronal tau pathology such as AT8+ cells with fine filamentous somatic protrusions or with disintegrating soma. We show that gradual dendritic atrophy is the first morphological sign of the degeneration of tangle-bearing neurons, even preceding axonal lesions. Interestingly, irrespective of the Braak NFT stage, tau pathology is more advanced in the dorsal LC that preferentially projects to vulnerable forebrain regions in Alzheimer's disease, like the hippocampus or neocortical areas, compared to the ventral LC projecting to the cerebellum and medulla. Moreover, already in the precortical Braak 0 stage, 3D analysis reveals clustering tendency and dendro-dendritic close appositions of AT8+ LC neurons, AT8+ long axons of NFT-bearing cells that join the ascending dorsal noradrenergic bundle after leaving the LC, as well as AT8+ processes of NFT-bearing LC neurons that target the 4th ventricle wall. Our study suggests that the unique cytoarchitecture, comprised of a densely packed and dendritically extensively interconnected neuronal network with long projections, makes the human LC to be an ideal anatomical template for early accumulation and trans-neuronal spreading of hyperphosphorylated tau.
13 citations
TL;DR: The importance of understanding the mechanisms through which catecholamines influence liver functions in order to draw benefit from the adrenergic and dopaminergic antagonists currently marketed is highlighted.
Abstract: Over the last few years, the number of research publications about the role of catecholamines (epinephrine, norepinephrine, and dopamine) in the development of liver diseases such as liver fibrosis, fatty liver diseases, or liver cancers is constantly increasing. However, the mechanisms involved in these effects are not well understood. In this review, we first recapitulate the way the liver is in contact with catecholamines and consider liver implications in their metabolism. A focus on the expression of the adrenergic and dopaminergic receptors by the liver cells is also discussed. Involvement of catecholamines in physiological (glucose metabolism, lipids metabolism, and liver regeneration) and pathophysiological (impact on drug-metabolizing enzymes expression, liver dysfunction during sepsis, fibrosis development, or liver fatty diseases and liver cancers) processes are then discussed. This review highlights the importance of understanding the mechanisms through which catecholamines influence liver functions in order to draw benefit from the adrenergic and dopaminergic antagonists currently marketed. Indeed, as these molecules are well-known drugs, their use as therapies or adjuvant treatments in several liver diseases could be facilitated.
10 citations
TL;DR: The 2022 metrics of the human proteome from the HUPO Human Proteome Project (HPP) show that protein expression has now been credibly detected (neXtProt PE1 level) for 18'407 (93.2%) of the 19'750 predicted proteins coded in the human genome, a net gain of 50 since 2021 from data sets generated around the world and reanalyzed by the HPP as mentioned in this paper.
Abstract: The 2022 Metrics of the Human Proteome from the HUPO Human Proteome Project (HPP) show that protein expression has now been credibly detected (neXtProt PE1 level) for 18 407 (93.2%) of the 19 750 predicted proteins coded in the human genome, a net gain of 50 since 2021 from data sets generated around the world and reanalyzed by the HPP. Conversely, the number of neXtProt PE2, PE3, and PE4 missing proteins has been reduced by 78 from 1421 to 1343. This represents continuing experimental progress on the human proteome parts list across all the chromosomes, as well as significant reclassifications. Meanwhile, applying proteomics in a vast array of biological and clinical studies continues to yield significant findings and growing integration with other omics platforms. We present highlights from the Chromosome-Centric HPP, Biology and Disease-driven HPP, and HPP Resource Pillars, compare features of mass spectrometry and Olink and Somalogic platforms, note the emergence of translation products from ribosome profiling of small open reading frames, and discuss the launch of the initial HPP Grand Challenge Project, "A Function for Each Protein".
10 citations
TL;DR: In this paper , the authors outline the evolution of these findings and provide updated neuroanatomical maps of sympathetic innervation and discuss the role of immune cells in regulating sympathetic terminals and metabolism, highlighting potential anti-obesity therapeutic approaches that emerge from the modern appreciation of SNS as a neural network vis a vis the historical fear of sympathomimetic pharmacology.
9 citations
TL;DR: The investigation of the sinusoidal network and DC/macrophage arrangements through the liver-CUBIC approach and whole-mount imaging provide a powerful platform for understanding hepatic circulatory properties and immune surveillance in the liver.
Abstract: Rational: The complex vascular architecture and diverse immune cells of the liver are critical for maintaining liver homeostasis. However, quantification of the network of liver vasculature and immunocytes at different scales from a single hepatic lobule to an intact liver lobe remains challenging. Methods: Here, we developed a fast and fluorescence-preserving transparency method, denoted liver-CUBIC, for systematic and integrated analysis of the microcirculation and the three-dimensional distribution of dendritic cells (DCs)/macrophages in intact liver lobes. Results: Whole-mount imaging at mesoscale revealed that the hepatic classical lobule preferred the oblate ellipsoid morphology in the mouse liver and exhibited hepatic sinusoids with heterogeneous arrangement and intricate loop structure. Liver fibrosis not only induces sinusoidal density increase but also promotes sinusoidal arrangement with increased sinusoidal branch and loop structure. Meanwhile, we found that CD11c+ DCs followed a lognormal distribution in the hepatic lobules, skewing toward lobular boundary in steady state. CCl4-induced chronic liver injury promoted CD11c+ DC rearrangement at the lobular border before the formation of liver fibrosis. Furthermore, through whole-mount imaging of tumor-immune cell-vascular crosstalk in intact lobes based on liver-CUBIC, we characterized an accumulation of CX3CR1+CCR2+F4/80+ macrophages at metastatic foci in early colorectal liver metastases. Importantly, colorectal cells secrete CCL2 to mobilize CX3CR1+CCR2+F4/80+ macrophages to accumulate at liver micrometastases, and the interruption of CCL2-induced macrophage accumulation inhibits early colonization of metastasis in the liver. Conclusions: Our investigation of the sinusoidal network and DC/macrophage arrangements through the liver-CUBIC approach and whole-mount imaging provide a powerful platform for understanding hepatic circulatory properties and immune surveillance in the liver.
4 citations
References
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TL;DR: Given the rapidly growing global burden of NAFLD and NASH, efforts must continue to find accurate non-invasive diagnostic and prognostic biomarkers, to develop effective treatments for individuals with advanced NASH and prevention methods for individuals at high risk of NA FLD and progressive liver disease.
1,173 citations
TL;DR: Nonalcoholic steatohepatitis is a major cause of cirrhosis and liver cancer and is associated with visceral adiposity and the metabolic syndrome and is nearly as common as type 2 diabetes.
Abstract: Nonalcoholic steatohepatitis is a major cause of cirrhosis and liver cancer. It is associated with visceral adiposity and the metabolic syndrome and is nearly as common as type 2 diabetes. Metabolic stress, inflammation, and fibrosis are the primary pathogenic mechanisms.
769 citations
TL;DR: The aim was to build an algorithm along with a scoring system for histopathologic classification of liver lesions that covers the entire spectrum of lesions in morbidly obese patients, and suggest describing liver lesions using the SAF score.
645 citations
TL;DR: A pipeline for high-speed acquisition of brain activity at cellular resolution through profiling immediate early gene expression using immunostaining and light-sheet fluorescence imaging, followed by automated mapping and analysis of activity by an open-source software program that is widely applicable to different experimental paradigms, including animal species for which transgenic activity reporters are not readily available.
581 citations
TL;DR: The histopathologic features of NAFLD/NASH and differential diagnostic considerations are discussed, and grading and staging schema proposed and currently in use are reviewed.
Abstract: Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are gaining increasing recognition as components of the emerging epidemic of obesity in North America and in other parts of the world. These entities are considered the hepatic manifestations of the insulin resistance syndrome and represent the spectra of fatty liver disease associated with it. All features of metabolic syndrome are associated with NAFLD/NASH, including obesity, type 2 diabetes, arterial hypertension, and hyperlipidemia in the form of elevated triglyceride levels. NAFLD/NASH can progress to liver cirrhosis and has been reported as a cause of hepatocellular carcinoma. In this review, the histopathologic features of NAFLD/NASH and differential diagnostic considerations are discussed. In addition, grading and staging schema proposed and currently in use are reviewed. Finally, other aspects for consideration by practicing pathologists, such as sampling issues, histopathologic findings after therapeutic interventions, and recurrence after liver transplantation, are addressed.
425 citations