Oral supplementation of choline attenuates the development of alcohol-related liver disease (ALD).

Background: Chronic alcohol intake is associated with alterations of choline metabolism in various tissues. Here, we assessed if an oral choline supplementation attenuated the development of alcohol-related liver disease (ALD) in mice.

Methods: Female C57BL/6 J mice (n = 8/group) were either pair-fed a liquid control diet, or a Lieber DeCarli liquid diet (5% ethanol) ± 2.

Long Noncoding RNAs in Diet-Induced Metabolic Diseases.

The prevalence of metabolic diseases, including type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD), is steadily increasing. Although many risk factors, such as obesity, insulin resistance, or hyperlipidemia, as well as several metabolic gene programs that contribute to the development of metabolic diseases are known, the underlying molecular mechanisms of these processes are still not fully understood. In recent years, it has become evident that not only protein-coding genes, but also noncoding genes, including a class of noncoding transcripts referred to as long noncoding RNAs (lncRNAs), play key roles in diet-induced metabolic disorders.

MASLD is related to impaired alcohol dehydrogenase (ADH) activity and elevated blood ethanol levels: Role of TNFα and JNK.

Elevated fasting ethanol levels in peripheral blood frequently found in metabolic dysfunction-associated steatohepatitis (MASLD) patients even in the absence of alcohol consumption are discussed to contribute to disease development. To test the hypothesis that besides an enhanced gastrointestinal synthesis a diminished alcohol elimination through alcohol dehydrogenase (ADH) may also be critical herein, we determined fasting ethanol levels and ADH activity in livers and blood of MASLD patients and in wild-type ± anti-TNFα antibody (infliximab) treated and TNFα mice fed a MASLD-inducing diet. Blood ethanol levels were significantly higher in patients and wild-type mice with MASLD while relative ADH activity in blood and liver tissue was significantly lower compared to controls.

Microbiota modulation by dietary oat beta-glucan prevents steatotic liver disease progression.

Background & Aims: Changes in gut microbiota in metabolic dysfunction-associated steatotic liver disease (MASLD) are important drivers of disease progression towards fibrosis. Therefore, reversing microbial alterations could ameliorate MASLD progression. Oat beta-glucan, a non-digestible polysaccharide, has shown promising therapeutic effects on hyperlipidemia associated with MASLD, but its impact on gut microbiota and most importantly MASLD-related fibrosis remains unknown.

Oral Supplementation of Phosphatidylcholine Attenuates the Onset of a Diet-Induced Metabolic Dysfunction-Associated Steatohepatitis in Female C57BL/6J Mice.

Background & Aims: Changes in phosphatidylcholine levels in the liver have been associated with the development of metabolic dysfunction-associated steatotic liver disease. Here, the effects of supplementing phosphatidylcholine on the development of early signs of metabolic dysfunction-associated steatohepatitis were assessed.

Methods: Male and female C57BL/6J mice were fed a liquid control or a fructose-, fat-, and/or cholesterol-rich diet for 7 or 8 weeks.

Supplementing L-Citrulline Can Extend Lifespan in and Attenuate the Development of Aging-Related Impairments of Glucose Tolerance and Intestinal Barrier in Mice.

L-Citrulline (L-Cit) is discussed to possess a protective effect on intestinal barrier dysfunction but also to diminish aging-associated degenerative processes. Here, the effects of L-Cit on lifespan were assessed in , while the effects of L-Cit on aging-associated decline were determined in C57BL/6J mice. For lifespan analysis, were treated with ±5 mM L-Cit.

TNFα is a key trigger of inflammation in diet-induced non-obese MASLD in mice.

Tumor necrosis factor alpha (TNFα) is thought to be a critical factor in the development of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we determined the effects of a treatment with the anti-TNFα antibody infliximab and a genetic deletion of TNFα, respectively, in the development of non-obese diet-induced early metabolic dysfunction-associated steatohepatitis (MASH) in mice. The treatment with infliximab improved markers of liver damage in mice with pre-existing early MASH.

Cognitive Alterations in Old Mice Are Associated with Intestinal Barrier Dysfunction and Induced Toll-like Receptor 2 and 4 Signaling in Different Brain Regions.

Emerging evidence implicate the 'microbiota-gut-brain axis' in cognitive aging and neuroinflammation; however, underlying mechanisms still remain to be elucidated. Here, we assessed if potential alterations in intestinal barrier function and microbiota composition as well as levels of two key pattern-recognition receptors namely Toll-like receptor (TLR) 2 and TLR4, in blood and different brain regions, and depending signaling cascades are paralleling aging associated alterations of cognition in healthy aging mice. Cognitive function was assessed in the Y-maze and intestinal and brain tissue and blood were collected in young (4 months old) and old (24 months old) male C57BL/6 mice to determine intestinal microbiota composition by Illumina amplicon sequencing, the concentration of TLR2 and TLR4 ligands in plasma and brain tissue as well as to determine markers of intestinal barrier function, senescence and TLR2 and TLR4 signaling.

Alcohol-related liver disease: also a question of what you drink?

Excessive alcohol intake is still among the leading causes of chronic liver diseases. Epidemiological studies suggest that per capita consumption of alcohol from various alcohol beverages e.g.

Impairments of intestinal arginine and NO metabolisms trigger aging-associated intestinal barrier dysfunction and 'inflammaging'.

Aging is considered a state of low grade inflammation, occurring in the absence of any overt infection often referred to as 'inflammaging'. Maintaining intestinal homeostasis may be a target to extend a healthier status in older adults. Here, we report that even in healthy older men low grade bacterial endotoxemia is prevalent.

GW9662, a peroxisome proliferator-activated receptor gamma antagonist, attenuates the development of non-alcoholic fatty liver disease.

Background And Aims: Insulin resistance is among the key risk factors for the development of non-alcoholic fatty liver disease (NAFLD). Recently, it has been reported that GW9662, shown to be a potent peroxisome proliferator-activated receptor gamma (PPARγ) antagonist, may improve insulin sensitivity in settings of type 2 diabetes. Here, we determined the effects of GW9662 on the development of NAFLD and molecular mechanisms involved.

The Intestinal Barrier Dysfunction as Driving Factor of Inflammaging.

The intestinal barrier, composed of the luminal microbiota, the mucus layer, and the physical barrier consisting of epithelial cells and immune cells, the latter residing underneath and within the epithelial cells, plays a special role in health and disease. While there is growing knowledge on the changes to the different layers associated with disease development, the barrier function also plays an important role during aging. Besides changes in the composition and function of cellular junctions, the entire gastrointestinal physiology contributes to essential age-related changes.

Alterations of nitric oxide homeostasis as trigger of intestinal barrier dysfunction in non-alcoholic fatty liver disease.

Changes in intestinal nitric oxide metabolism are discussed to contribute for the development of intestinal barrier dysfunction in non-alcoholic fatty liver disease (NAFLD). To induce steatosis, female C57BL/6J mice were pair-fed with a liquid control diet (C) or a fat-, fructose- and cholesterol-rich diet (FFC) for 8 weeks. Mice received the diets ± 2.

Toll-like receptor 1 as a possible target in non-alcoholic fatty liver disease.

Toll-like receptors (TLRs) in the liver compartment have repeatedly been attributed to the development of non-alcoholic fatty liver disease (NAFLD). Knowledge on TLR expression in blood cells and their relation to intestinal microbiota and NAFLD development is limited. Here, we determined TLR expression patterns in peripheral blood mononuclear cells (PBMCs) of NAFLD patients and controls, their relation to intestinal microbiota and the impact of TLRs found altered in NAFLD development.

Markers of Intestinal Permeability Are Rapidly Improved by Alcohol Withdrawal in Patients with Alcohol-Related Liver Disease.

Changes in intestinal microbiome and barrier function are critical in the development of alcohol-related liver disease (ALD). Here, we determined the effects of a one-week alcohol withdrawal on parameters of intestinal barrier function in heavy drinkers with ALD in comparison to healthy non-drinkers (controls). In serum samples of 17 controls (m = 10/f = 7) and 37 age-matched ALD patients (m = 26/f = 11) undergoing a one-week alcohol withdrawal, markers of liver health and intestinal barrier function were assessed.

Effects of different standard and special diets on cognition and brain mitochondrial function in mice.

Human nutrition plays an important role in prevention or at least slowing down the progression of age- and diet-related diseases. Thereby, mitochondrial dysfunction represents one common underlying mechanism, which is being investigated in mouse models. However, the influence of the selected diets in preclinical studies on cognition and mitochondrial function has not yet been reported cohesively.

Microbiota profiling in aging-associated inflammation and liver degeneration.

Background: The number of people above the age of 60 years is raising world-wide being associated with an increase in the prevalence of aging-associated impairments and even diseases. Recent studies suggest that aging is associated with alterations in bacterial endotoxin levels and that these changes may add to low-grade inflammation, the so-called 'inflammaging', and aging-associated liver degeneration. However, mechanisms involved, and especially, the interaction of intestinal microbiota and barrier in the development of aging-associated inflammation and liver degeneration have not been fully understood.

Fortifying Butterfat with Soybean Oil Attenuates the Onset of Diet-Induced Non-Alcoholic Steatohepatitis and Glucose Intolerance.

The addition of plant oils such as soybean oil (S) to a diet rich in saturated fatty acids is discussed as a possible route to prevent or diminish the development of metabolic disease. Here, we assessed whether a butterfat-rich diet fortified with S affects the development of early non-alcoholic steatohepatitis (NASH) and glucose intolerance. Female C57BL/6J mice were fed a standard-control diet (C); a fat-, fructose-, and cholesterol-rich diet (FFC, 25E% butterfat, 50% (wt.

Citrulline supplementation attenuates the development of non-alcoholic steatohepatitis in female mice through mechanisms involving intestinal arginase.

Non-alcoholic fatty liver disease (NAFLD) is by now the most prevalent liver disease worldwide. The non-proteogenic amino acid l-citrulline (L-Cit) has been shown to protect mice from the development of NAFLD. Here, we aimed to further assess if L-Cit also attenuates the progression of a pre-existing diet-induced NAFLD and to determine molecular mechanisms involved.

Exchanging dietary fat source with extra virgin olive oil does not prevent progression of diet-induced non-alcoholic fatty liver disease and insulin resistance.

Dietary fat is discussed to be critical in the development of non-alcoholic fatty liver disease. Here, we assess the effect of exchanging dietary fat source from butterfat to extra virgin olive oil on the progression of an already existing diet-induced non-alcoholic fatty liver disease in mice. Female C57BL/6J mice were fed a liquid butterfat-, fructose- and cholesterol-rich diet (BFC, 25E% from butterfat) or control diet (C, 12%E from soybean oil) for 13 weeks.

Fortifying diet with rapeseed oil instead of butterfat attenuates the progression of diet-induced non-alcoholic fatty liver disease (NAFLD) and impairment of glucose tolerance.

Background: Absolute dietary fat intake but even more so fatty acid pattern is discussed to be critical in the development of non-alcoholic fatty liver disease (NAFLD). Here, we determined if switching a butterfat enriched diet to a rapeseed oil (RO) enriched diet affects progression of an existing NAFLD and glucose intolerance in mice.

Methods: For eight weeks, female C57Bl/6J mice were either fed a liquid control (C) or a butterfat-, fructose- and cholesterol-rich diet (BFC, 25E% butterfat) to induce early signs of steatohepatitis and glucose intolerance in mice.

Oral Supplementation of Sodium Butyrate Attenuates the Progression of Non-Alcoholic Steatohepatitis.

Sodium butyrate (SoB) supplementation has been suggested to attenuate the development of non-alcoholic fatty liver disease (NAFLD). Here, we determined the therapeutic potential of SoB on NAFLD progression and molecular mechanism involved. Eight-week old C57BL/6J mice were pair-fed a fat-, fructose- and cholesterol-rich diet (FFC) or control diet (C).

Aging-related liver degeneration is associated with increased bacterial endotoxin and lipopolysaccharide binding protein levels.

Aging is a risk factor in the development of many diseases, including liver-related diseases. The two aims of the present study were ) to determine how aging affects liver health in mice in the absence of any interventions and ) if degenerations observed in relation to blood endotoxin levels are critical in aging-associated liver degeneration. Endotoxin levels and markers of liver damage, mitochondrial dysfunction, insulin resistance, and apoptosis as well as the Toll-like receptor 4 (Tlr-4) signaling cascade were studied in liver tissue and blood, respectively, of 3- and 24-mo-old male C57BL/6J mice.