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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.)

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.)

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.)