Metabolic stress drives sympathetic neuropathy within the liver

Liu, Kaili; Yang, Lu; Wang, Gang; Liu, Jiaqi; Zhao, Xuan; Wang, Yi; Li, Jiali; Yang, Jing

doi:10.1016/j.cmet.2021.01.012

Cited by 68 publications

(60 citation statements)

References 55 publications

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“…More specifically, albeit our experiments concluded that SNAP-25b deficiency per se does not affect the integrity of the liver sympathetic nerves, we cannot totally exclude the possibility that during WD (under metabolic challenge), the SNAP-25b–deficient condition might contribute to the increased vulnerability of the hepatic NAergic innervation. At the same time, our data on human livers provide translational relevance of the results with experimental NAFLD, and a recently published paper ( 50 ) also supports the presence of sympathetic nerve atrophy in the mouse fatty liver.…”

Section: Discussionsupporting

confidence: 84%

“…Studies applying VAChT immunohistochemistry did not find cholinergic nerves in rat ( 48 ) or mouse ( 49 ) liver. A recent volume imaging study also failed to detect cholinergic innervations in the mouse, rhesus macaque monkey, and human liver ( 50 ). Moreover, studies applying hepatic vagotomy and reporting its physiological consequences may be taken with caution, since hepatic parasympathetic denervation actually lesions the common hepatic vagus branch, including also the gastroduodenal branch that innervates parts of the distal stomach, pylorus, duodenum, and pancreas ( 51 , 52 ).…”

Section: Discussionmentioning

confidence: 99%

“…In these steatohepatitic livers, no proximal sprouting or increase in NGF expressions is detected; the NAergic innervation is apparently collapsing. After submission of the present work, a paper was published where the authors describe liver sympathetic neuropathy in mice kept on a 20- to 24-week high-fat diet as well as in 12-week-old ob/ob and db/db mice, applying volume imaging technology ( 50 ). While this study of Liu et al ( 50 ) lacks detailed qualitative or quantitative characterization of the fiber dystrophy and its comparison with the hepatic NAFLD spectrum pathology, the authors demonstrate, with a series of elegant experiments, that the noticed fiber damage can be reversed by calorie restriction or neutralizing TNFα antibody treatment in mice previously fed with a high-fat diet or by recombinant leptin treatment of ob/ob mice.…”

Section: Discussionmentioning

confidence: 99%

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Disorganization and degeneration of liver sympathetic innervations in nonalcoholic fatty liver disease revealed by 3D imaging

et al. 2021

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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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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Disorganization and degeneration of liver sympathetic innervations in nonalcoholic fatty liver disease revealed by 3D imaging

et al. 2021

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“…Interestingly, TNF-α also seems to function upstream of SARM1. The Yang lab has recently shown that TNF-α mediates axonal loss via SARM1 in mice liver (Liu et al, 2021), consistent with the finding that TNF-α induces SARM1-dependent axon degeneration in sensory neurons (Ko et al, 2020).…”

Section: Negative Regulation By Sterile Alpha and Toll/ Interleukin-1 Receptor Motif-containing 1 In Toll-like Receptor Signalingsupporting

confidence: 71%

A Novel NAD Signaling Mechanism in Axon Degeneration and its Relationship to Innate Immunity

Hopkins

Kobe

et al. 2021

Front. Mol. Biosci.

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Axon degeneration represents a pathological feature of many neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease where axons die before the neuronal soma, and axonopathies, such as Charcot-Marie-Tooth disease and hereditary spastic paraplegia. Over the last two decades, it has slowly emerged that a central signaling pathway forms the basis of this process in many circumstances. This is an axonal NAD-related signaling mechanism mainly regulated by the two key proteins with opposing roles: the NAD-synthesizing enzyme NMNAT2, and SARM1, a protein with NADase and related activities. The crosstalk between the axon survival factor NMNAT2 and pro-degenerative factor SARM1 has been extensively characterized and plays an essential role in maintaining the axon integrity. This pathway can be activated in necroptosis and in genetic, toxic or metabolic disorders, physical injury and neuroinflammation, all leading to axon pathology. SARM1 is also known to be involved in regulating innate immunity, potentially linking axon degeneration to the response to pathogens and intercellular signaling. Understanding this NAD-related signaling mechanism enhances our understanding of the process of axon degeneration and enables a path to the development of drugs for a wide range of neurodegenerative diseases.

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“…However, recent preclinical evidence suggests that diabetic neuropathy also affects the liver. In particular, a recent report indicates that 20 weeks of high-fat diet (HFD) results in hepatic sympathetic neuropathy in mice ( 36 ). Mice deficient for the leptin gene ( ob/ob ) also exhibited a significant reduction of sympathetic axons in the liver ( 36 ).…”

Section: Hepatic Diabetic Neuropathymentioning

confidence: 99%

Pathophysiological Mechanisms That Alter the Autonomic Brain-Liver Communication in Metabolic Diseases

Silva

Caron

2021

Endocrinology

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The brain influences liver metabolism through many neuroendocrine and autonomic mechanisms that have evolved to protect the organism against starvation and hypoglycemia. Unfortunately, what is normally an effective way to prevent death has become dysregulated in modern obesogenic environments, but the pathophysiological mechanisms behind metabolic dyshomeostasis are still unclear. In this Mini-Review, we provide our thoughts regarding obesity and type 2 diabetes as diseases of the autonomic nervous system. We discuss the pathophysiological mechanisms that alter the autonomic brain-liver communication in these diseases, and how they could represent important targets to prevent or treat metabolic dysfunctions. We discuss how sympathetic hyperactivity to the liver may represent an early event in the progression of metabolic diseases and could progressively lead to hepatic neuropathy. We hope that this discussion will inspire and help framing a model on the importance of better understanding the chronology of autonomic dysfunctions in the liver in order to apply the right strategy at the right time.

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Metabolic stress drives sympathetic neuropathy within the liver

Cited by 68 publications

References 55 publications

Disorganization and degeneration of liver sympathetic innervations in nonalcoholic fatty liver disease revealed by 3D imaging

Disorganization and degeneration of liver sympathetic innervations in nonalcoholic fatty liver disease revealed by 3D imaging

A Novel NAD Signaling Mechanism in Axon Degeneration and its Relationship to Innate Immunity

Pathophysiological Mechanisms That Alter the Autonomic Brain-Liver Communication in Metabolic Diseases

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