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Extensive research has demonstrated endurance exercise to be neuroprotective. Whether these neuroprotective benefits are mediated, in part, by hepatic ketone production remains unclear. To investigate the role of hepatic ketone production on brain health during exercise, healthy 6-month-old female rats underwent viral knockdown of the rate-limiting enzyme in the liver that catalyses the first reaction in ketogenesis: 3-hydroxymethylglutaryl-CoA synthase 2 (HMGCS2). Rats were then subjected to either a bout of acute exercise or 4 weeks of chronic treadmill running (5 days/week) and cognitive behavioural testing. Acute exercise elevated ketone plasma concentration 1 h following exercise. Hepatic HMGCS2 knockdown, verified by protein expression, reduced ketone plasma concentration 1 h after acute exercise and 48 h after chronic exercise. Proteomic analysis and enrichment of the frontal cortex revealed hepatic HMGCS2 knockdown reduced markers of mitochondrial function 1 h after acute exercise. HMGCS2 knockdown significantly reduced state 3 complex I + II respiration in isolated mitochondria from the frontal cortex after chronic exercise. Spatial memory and protein markers of synaptic plasticity were significantly reduced by HMGCS2 knockdown. These deficiencies were prevented by chronic endurance exercise training. In summary, these are the first data to propose that hepatic ketogenesis is required to maintain cognition and mitochondrial function, irrespective of training status, and that endurance exercise can overcome neuropathology caused by insufficient hepatic ketogenesis. These results establish a mechanistic link between liver and brain health that enhance our understanding of how peripheral tissue metabolism influences brain health. KEY POINTS: Decades of literature demonstrate endurance exercise to be neuroprotective. Whether neuroprotective benefits are mediated, in part, by hepatic ketone production remains unclear. This study provides the first set of data that suggest hepatic ketogenesis is required to maintain cognition, synaptic plasticity and mitochondrial function. These data indicate endurance exercise can protect against cognitive decline caused by compromised hepatic ketogenesis. These results establish a mechanistic link between liver and brain function, prompting further investigation of how hepatic metabolism influences brain health., (© 2025 The Authors. The Journal of Physiology © 2025 The Physiological Society.)

Background & Aims: Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is an extracellular matrix regulator with anti-fibrotic effects. However, its expression and role in metabolic dysfunction-associated steatohepatitis (MASH) and hepatic fibrosis are poorly understood., Methods: We generated a novel transgenic mouse model with RECK overexpression specifically in hepatocytes to investigate its role in Western diet (WD)-induced liver disease. Proteomic analysis and in vitro studies were performed to mechanistically link RECK to hepatic inflammation and fibrosis., Results: Our results show that RECK expression is significantly decreased in liver biopsies from human patients diagnosed with MASH and correlated negatively with severity of metabolic dysfunction-associated steatotic liver disease (MASLD) and fibrosis. Similarly, RECK expression is downregulated in WD-induced MASH in wild-type mice. Hepatocyte-specific RECK overexpression significantly reduced hepatic pathology in WD-induced liver injury. Proteomic analysis highlighted changes in extracellular matrix and cell-signaling proteins. In vitro mechanistic studies linked RECK induction to reduced ADAM10 (a disintegrin and metalloproteinase domain-containing protein 10) and ADAM17 activity, amphiregulin release, epidermal growth factor receptor activation, and stellate cell activation., Conclusion: Our in vivo and mechanistic in vitro studies reveal that RECK is a novel upstream regulator of inflammation and fibrosis in the diseased liver, its induction is hepatoprotective, and thus highlights its potential as a novel therapeutic in MASH., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The association between liver and brain health has gained attention as biomarkers of liver function have been revealed to predict neurodegeneration. The liver is a central regulator in metabolic homeostasis. However, in nonalcoholic fatty liver disease (NAFLD), homeostasis is disrupted which can result in extrahepatic organ pathologies. Emerging literature provides insight into the mechanisms behind the liver-brain health axis. These include the increased production of liver-derived factors that promote insulin resistance and loss of neuroprotective factors under conditions of NAFLD that increase insulin resistance in the central nervous system. In addition, elevated proinflammatory cytokines linked to NAFLD negatively impact the blood-brain barrier and increase neuroinflammation. Furthermore, exacerbated dyslipidemia associated with NAFLD and hepatic dysfunction can promote altered brain bioenergetics and oxidative stress. In this review, we summarize the current knowledge of the crosstalk between liver and brain as it relates to the pathophysiology between NAFLD and neurodegeneration, with an emphasis on Alzheimer's disease. We also highlight knowledge gaps and future areas for investigation to strengthen the potential link between NAFLD and neurodegeneration., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: Endothelial nitric oxide synthase (eNOS) is a potential mediator of exercise-induced hepatic mitochondrial adaptations., Methods: Here, male and female hepatocyte-specific eNOS knockout (eNOS hep-/- ) and intact hepatic eNOS (eNOS fl/fl ) mice performed voluntary wheel-running exercise (EX) or remained in sedentary cage conditions for 10 weeks., Results: EX resolved the exacerbated hepatic steatosis in eNOS hep-/- male mice. Elevated hydrogen peroxide emission (~50% higher in eNOS hep-/- vs. eNOS fl/fl mice) was completely ablated with EX. Interestingly, EX increased [1- 14 C] palmitate oxidation in eNOS fl/fl male mice, but this was blunted in the eNOS hep-/- male mice. eNOS hep-/- mice had lower markers of the energy sensors AMP-activated protein kinase (AMPK)/phospho- (p)AMPK and mammalian target of rapamycin (mTOR) and p-mTOR, as well as the autophagy initiators serine/threonine-protein kinase ULK1 and pULK1, compared with eNOS fl/fl mice. Females showed elevated electron transport chain protein content and markers of mitochondrial biogenesis (transcription factor A, mitochondrial, peroxisome proliferator-activated receptor-gamma coactivator 1α)., Conclusions: Collectively, this study demonstrates for the first time, to the authors' knowledge, the requirement of eNOS in hepatocytes in the EX-induced increases in hepatic fatty acid oxidation in male mice. Deletion of eNOS in hepatocytes also appears to impair the energy-sensing ability of the cell and inhibit the activation of the autophagy initiating factor ULK1. These data uncover the important and novel role of hepatocyte eNOS in EX-induced hepatic mitochondrial adaptations., (© 2022 The Obesity Society.)

Regulation of endothelial nitric oxide synthase (eNOS) in hepatocytes may be an important target in nonalcoholic fatty liver disease (NAFLD) development and progression to nonalcoholic steatohepatitis (NASH). In this study, we show genetic deletion and viral knockdown of hepatocyte-specific eNOS exacerbated hepatic steatosis and inflammation, decreased hepatic mitochondrial fatty acid oxidation and respiration, increased mitochondrial H 2 O 2 emission, and impaired the hepatic mitophagic (BNIP3 and LC3II) response. Conversely, overexpressing eNOS in hepatocytes in vitro and in vivo increased hepatocyte mitochondrial respiration and attenuated Western diet-induced NASH. Moreover, patients with elevated NAFLD activity score (histology score of worsening steatosis, hepatocyte ballooning, and inflammation) exhibited reduced hepatic eNOS expression, which correlated with reduced hepatic mitochondrial fatty acid oxidation and lower hepatic protein expression of mitophagy protein BNIP3. The current study reveals an important molecular role for hepatocyte-specific eNOS as a key regulator of NAFLD/NASH susceptibility and mitochondrial quality control with direct clinical correlation to patients with NASH., (© 2021 by the American Diabetes Association.)

Non-alcoholic fatty liver disease (NAFLD) is a multimorbidity disorder ranging from excess accumulation of fat in the liver (steatosis) to steatohepatitis (NASH) and end-stage cirrhosis, and the development of hepatocellular carcinoma (HCC) in a subset of patients. The defining features of NASH are inflammation and progressive fibrosis. Currently, no pharmaceutical therapies are available for NAFLD, NASH and HCC; therefore, developing novel treatment strategies is desperately needed. Reversion Inducing Cysteine Rich Protein with Kazal motifs (RECK) is a well-known modifier of the extracellular matrix in hepatic remodeling and transition to HCC. More recently, its role in regulating inflammatory and fibrogenic processes has emerged. Here, we summarize the most relevant findings that extend our current understanding of RECK as a regulator of inflammation and fibrosis, and its induction as a potential strategy to blunt the development and progression of NASH and HCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dashek, Diaz, Chandrasekar and Rector.)

The intestinal microbiota of an organism can significantly alter outcome data in otherwise identical experiments. Occasionally, animals may require sedation or anesthesia for scientific or health-related purposes, and certain anesthetics, such as ketamine, can profoundly affect the gastrointestinal system. While many factors can alter the gut microbiome (GM), the effects of anesthetics on the composition or diversity of the GM have not been established. The goal of the current study was to determine whether daily administration of ketamine would significantly alter the microbiome of CD1 mice. To achieve this goal, female CD1 mice received daily injections of ketamine HCl (100 mg/kg) or the equivalent volume of 0.9% saline for 10 consecutive days. Fecal samples were collected before the first administration and 24 h after the final dose of either ketamine or saline. Samples were analyzed by 16S rRNA sequencing to identify changes between groups in diversity or composition of GM. The study found no significant changes to the GM after serial ketamine administration when treated mice were housed with controls. Therefore, ketamine administration is unlikely to alter the GM of a CD1 mouse and should not serve be a confounding factor in reproducibility of research.

Nonalcoholic fatty liver disease (NAFLD) is a major health problem, and its prevalence has increased in recent years, concurrent with rising rates of obesity and other metabolic diseases. Currently, there are no FDA-approved pharmacological therapies for NAFLD, and lifestyle interventions, including weight loss and exercise, remain the cornerstones for treatment. Manipulating diet composition and eating patterns may be a sustainable approach to NAFLD treatment. Dietary strategies including Paleolithic, ketogenic, Mediterranean, high-protein, plant-based, low-carbohydrate, and intermittent fasting diets have become increasingly popular because of their purported benefits on metabolic disease. This review highlights what is currently known about these popular dietary approaches in the management of NAFLD in clinical populations with mechanistic insight from animal studies. It also identifies key knowledge gaps to better inform future preclinical and clinical studies aimed at the treatment of NAFLD., (© 2020 The Obesity Society.)

Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest.

Purpose: To test a hypothesis of regional variation in the effect of experimental glaucoma on choroidal blood flow (ChBF) and retinal function., Methods: Five rhesus macaques underwent laser trabecular destruction (LTD) to induce elevated intraocular pressure (IOP). Intraocular pressures were elevated for 56 to 57 weeks. Multifocal electroretinographic (mfERG) and multifocal visual evoked cortical potential (mfVEP) testing were performed at regular intervals before and during the period of IOP elevation. At euthanasia, the IOP was manometrically controlled at 35 (experimentally glaucomatous eye) and 15 (fellow control eye) mm Hg. Fluorescent microspheres were injected into the left ventricle. Regional ChBF was determined., Results: All of the experimentally glaucomatous eyes exhibited supranormal first-order kernel (K1) root mean square (RMS) early portions of the mfERG waveforms and decreased amplitudes of the late waveforms. The supranormality was somewhat greater in the central macula. Second-order kernel, first slice (K2.1) RMS mfVEP response was inversely correlated (R(2) = 0.97) with axonal loss. Total ChBF was reduced in the experimentally glaucomatous eyes. The mean blood flow was 893 ± 123 and 481 ± 37 μL/min in the control and glaucomatous eyes, respectively. The ChBF showed regional variability with the greatest proportional decrement most often found in the central macula., Conclusions: This is the first demonstration of globally reduced ChBF in chronic experimental glaucoma in the nonhuman primate. Both the alteration of mfERG waveform components associated with outer retinal function and the reduction in ChBF were greatest in the macula, suggesting that there may be a spatial colocalization between ChBF and some outer retinal effects in glaucoma., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

Purpose: Outer retinal injury has been well described in glaucoma. To better understand the source of this injury, we wanted to develop a reliable model of partial retinal ganglion cell (RGC) axotomy., Methods: Endodiathermy spots were placed along the inferior 180° adjacent to the optic nerve margin in the right eyes of four cynomolgus monkeys. Fluorescein angiography, spectral domain optical coherence tomography (SD-OCT), and multifocal electroretinography (mfERG) were performed at various intervals. Two animals were sacrificed at 3 months. Two animals were sacrificed at 4 months, at which time they underwent an injection of fluorescent microspheres to measure regional choroidal blood flow. Retinal immunohistochemistry for glial fibrillary acidic protein (GFAP), rhodopsin, S-cone opsin, and M/L-cone opsin were performed, as were axon counts of the optic nerves., Results: At 3 months, there was marked thinning of the inferior nerve fiber layer on SD-OCT. The mfERG waveforms were consistent with inner but not outer retinal injury. Greater than 95% reduction in axons was seen in the inferior optic nerves but no secondary degeneration superiorly. There was marked thinning of the nerve fiber and ganglion cell layers in the inferior retinas. However, the photoreceptor histology was similar in the axotomized and nonaxotomized areas. Regional choroidal blood flow was not affected by the axotomy., Conclusions: Unlike experimental glaucoma, hemiretinal endodiathermy axotomy (HEA) of the RGCs produces no apparent anatomic, functional, or blood flow effects on the outer retina and choroid.