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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 H2O2 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.

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 due to their purported benefits on metabolic disease. In this review, we will highlight what is currently known about these popular dietary approaches in the management of NAFLD in clinical populations with mechanistic insight from animal studies. We will also identify key knowledge gaps to better inform future preclinical and clinical studies aimed at the treatment of NAFLD.

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.