Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and represents a growing challenge in terms of prevention and treatment. Despite its high prevalence, only a small minority of affected patients develops inflammation and subsequently fibrosis and chronic liver disease, while most of them only exhibit simple steatosis. In this context, the full understanding of the mechanisms underlying the development of NAFLD and non-alcoholic steatohepatitis (NASH) is of extreme importance; despite advances in this field, knowledge on the pathogenesis of NAFLD is still incomplete. The 'two-hit' hypothesis is now obsolete, as it is inadequate to explain the several molecular and metabolic changes that take place in NAFLD. The "multiple hit" hypothesis considers multiple insults acting together on genetically predisposed subjects to induce NAFLD and provides a more accurate explanation of NAFLD pathogenesis. Such hits include insulin resistance, hormones secreted from the adipose tissue, nutritional factors, gut microbiota and genetic and epigenetic factors. In this article, we review the factors that form this hypothesis.

/pdf/the-multiple-hit-pathogenesis-of-non-alcoholic-fatty-liver-4b2gfxdwuu.pdf

The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)

The liver is an essential metabolic organ, and its metabolic function is controlled by insulin and other metabolic hormones. Glucose is converted into pyruvate through glycolysis in the cytoplasm, and pyruvate is subsequently oxidized in the mitochondria to generate ATP through the TCA cycle and oxidative phosphorylation. In the fed state, glycolytic products are used to synthesize fatty acids through de novo lipogenesis. Long-chain fatty acids are incorporated into triacylglycerol, phospholipids, and/or cholesterol esters in hepatocytes. These complex lipids are stored in lipid droplets and membrane structures, or secreted into the circulation as very low-density lipoprotein particles. In the fasted state, the liver secretes glucose through both glycogenolysis and gluconeogenesis. During pronged fasting, hepatic gluconeogenesis is the primary source for endogenous glucose production. Fasting also promotes lipolysis in adipose tissue, resulting in release of nonesterified fatty acids which are converted into ketone bodies in hepatic mitochondria though β-oxidation and ketogenesis. Ketone bodies provide a metabolic fuel for extrahepatic tissues. Liver energy metabolism is tightly regulated by neuronal and hormonal signals. The sympathetic system stimulates, whereas the parasympathetic system suppresses, hepatic gluconeogenesis. Insulin stimulates glycolysis and lipogenesis but suppresses gluconeogenesis, and glucagon counteracts insulin action. Numerous transcription factors and coactivators, including CREB, FOXO1, ChREBP, SREBP, PGC-1α, and CRTC2, control the expression of the enzymes which catalyze key steps of metabolic pathways, thus controlling liver energy metabolism. Aberrant energy metabolism in the liver promotes insulin resistance, diabetes, and nonalcoholic fatty liver diseases.

Energy metabolism in the liver

NAFLD is a spectrum of progressive liver disease that encompasses simple steatosis, NASH, fibrosis and, ultimately, cirrhosis. NAFLD is recognized as the hepatic component of the metabolic syndrome, as these conditions have insulin resistance as a common pathophysiological mechanism. Therefore, NAFLD is strongly associated with type 2 diabetes mellitus and abdominal obesity. As lifestyles have become increasingly sedentary and dietary patterns have changed, the worldwide prevalence of NAFLD has increased dramatically and is projected to be the principal aetiology for liver transplantation within the next decade. Importantly, a growing body of clinical and epidemiological evidence suggests that NAFLD is associated not only with liver-related morbidity and mortality, but also with an increased risk of developing both cardiovascular disease and type 2 diabetes mellitus. This article reviews the evidence that suggests NAFLD is a multisystem disease and the factors that might determine interindividual variation in the development and progression of its major hepatic and extrahepatic manifestations (principally type 2 diabetes mellitus and cardiovascular disease).

Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis.

Data are accumulating that emphasize the important role of the intestinal barrier and intestinal permeability for health and disease. However, these terms are poorly defined, their assessment is a matter of debate, and their clinical significance is not clearly established. In the present review, current knowledge on mucosal barrier and its role in disease prevention and therapy is summarized. First, the relevant terms ‘intestinal barrier’ and ‘intestinal permeability’ are defined. Secondly, the key element of the intestinal barrier affecting permeability are described. This barrier represents a huge mucosal surface, where billions of bacteria face the largest immune system of our body. On the one hand, an intact intestinal barrier protects the human organism against invasion of microorganisms and toxins, on the other hand, this barrier must be open to absorb essential fluids and nutrients. Such opposing goals are achieved by a complex anatomical and functional structure the intestinal barrier consists of, the functional status of which is described by ‘intestinal permeability’. Third, the regulation of intestinal permeability by diet and bacteria is depicted. In particular, potential barrier disruptors such as hypoperfusion of the gut, infections and toxins, but also selected over-dosed nutrients, drugs, and other lifestyle factors have to be considered. In the fourth part, the means to assess intestinal permeability are presented and critically discussed. The means vary enormously and probably assess different functional components of the barrier. The barrier assessments are further hindered by the natural variability of this functional entity depending on species and genes as well as on diet and other environmental factors. In the final part, we discuss selected diseases associated with increased intestinal permeability such as critically illness, inflammatory bowel diseases, celiac disease, food allergy, irritable bowel syndrome, and – more recently recognized – obesity and metabolic diseases. All these diseases are characterized by inflammation that might be triggered by the translocation of luminal components into the host. In summary, intestinal permeability, which is a feature of intestinal barrier function, is increasingly recognized as being of relevance for health and disease, and therefore, this topic warrants more attention.

/pdf/intestinal-permeability-a-new-target-for-disease-prevention-1k5hgcc958.pdf

Intestinal permeability – a new target for disease prevention and therapy

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.23719

Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: The central role of nontriglyceride fatty acid metabolites

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.23122

Toll-like receptor 4 is involved in the development of fructose-induced hepatic steatosis in mice.

Elevated dietary fructose intake, altered intestinal motility, and barrier function may be involved in the development of nonalcoholic fatty liver disease (NAFLD). Because intestinal motility and p...

Serotonin reuptake transporter (SERT) plays a critical role in the onset of fructose-induced hepatic steatosis in mice

Background
Enterochromaffin cells and enteric neurons synthesize and release serotonin (5-HT). Reuptake, mediated by a plasmalemmal transporter (SERT) terminates the action of released 5-HT. Serotonin secretion and serotonin reuptake transporter (SERT) expression have been reported to be decreased in TNBS-induced experimental colitis and in patients with ulcerative colitis. The present study was designed to utilize the transgenic deletion of SERT as a gain-of-function model to test the hypothesis that 5-HT is a pro-inflammatory mediator in experimental colitis.

/pdf/enhancement-of-intestinal-inflammation-in-mice-lacking-8f7ktz0c84.pdf

Enhancement of intestinal inflammation in mice lacking interleukin 10 by deletion of the serotonin reuptake transporter

Obesity is a major cause for nonalcoholic fatty liver disease (NAFLD). Previous studies suggested that alterations in intestinal motility and permeability contribute to the development of NAFLD. Serotonin and serotonin receptor type 3 (5-HT3R) are key factors in the regulation of intestinal motility and permeability. Therefore, we studied the effect of the 5-HT3R antagonists tropisetron and palonosetron on the development of NAFLD in leptin-deficient obese mice. Four-week-old ob/ob mice and lean controls were treated for 6 weeks orally with tropisetron or palonosetron at 0.2 mg/kg per day. We determined markers of liver damage and inflammation, portal endotoxin levels, and duodenal concentrations of serotonin, serotonin-reuptake transporter (SERT), occludin, and claudin-1. Tropisetron treatment significantly reduced liver fat content (−29%), liver inflammation (−56%), and liver cell necrosis (−59%) in ob/ob mice. The beneficial effects of tropisetron were accompanied by a decrease in plasma alanine aminotransferase and portal vein plasma endotoxin levels, an attenuation of enhanced MyD88 and tumor necrosis factor-α mRNA expression in the liver, and an increase of tight junction proteins in the duodenum. Tropisetron treatment also caused a reduction of elevated serotonin levels and an increase of SERT in the duodenum of ob/ob mice. Palonosetron had similar effects as tropisetron with regard to the reduction of liver fat and other parameters. Tropisetron and palonosetron are effective in attenuating NAFLD in a genetic mouse model of obesity. The effect involves the intestinal nervous system, resulting in a reduction of endotoxin influx into the liver and subsequently of liver inflammation and fat accumulation.

https://jpet.aspetjournals.org/content/jpet/early/2011/09/08/jpet.111.181834.full.pdf

Serotonin Receptor Type 3 Antagonists Improve Obesity-Associated Fatty Liver Disease in Mice

Saturated fatty acids are thought to be of relevance for the development of non-alcoholic fatty liver disease and obesity However, the underlying mechanisms are poorly understood In previous studies we found that food-derived carbohydrates such as fructose alter the intestinal serotonergic system while inducing fatty liver disease in mice Here, we examined the effect of fatty acid quantity (11% versus 15%) and quality (saturated, monounsaturated, or polyunsaturated fatty acids) on hepatic fat accumulation, intestinal barrier and the intestinal serotonergic system C57BL/6 mice had free access to diets enriched with one of the three fatty acids or standard diet, for 8 weeks In an additional experiment mice were fed diets enriched with saturated, monounsaturated fatty acids or standard diet supplemented with tryptophan (04 g/(kgd), 8 weeks) or not Hepatic fat accumulation, small intestinal barrier impairment and components of the serotonergic system were measured with RT-PCR, western blot or immunoassays For statistical analysis t-test and one-way ANOVA with Tukey’s post hoc test and Bartlett’s test for equal variances was used Hepatic triglycerides, liver weight and liver to body weight ratio were significantly changed depending on the fat quality but not fat quantity In contrast, fat quantity but not quality decreased the expression of the tight junction proteins occludin and claudin-1 in the small intestine These changes seemed to result in enhanced portal vein endotoxin concentrations and fatty liver disease after feeding diet enriched with saturated and monounsaturated fatty acids but not polyunsaturated fatty acids Neither fatty acid quantity nor quality significantly influenced the intestinal serotonergic system Similarly, tryptophan supplementation had no impact on small intestinal barrier or fatty liver disease In conclusion, diets rich in saturated or monounsaturated fatty acids promote the development of fatty liver disease in mice, likely by a dysfunction of the small intestinal mucosal barrier

/pdf/role-of-serotonin-in-fatty-acid-induced-non-alcoholic-fatty-1mhg0txeim.pdf

Synia Haub

Papers

Toll-like receptor 4 is involved in the development of fructose-induced hepatic steatosis in mice.

Serotonin reuptake transporter (SERT) plays a critical role in the onset of fructose-induced hepatic steatosis in mice

Enhancement of intestinal inflammation in mice lacking interleukin 10 by deletion of the serotonin reuptake transporter

Serotonin Receptor Type 3 Antagonists Improve Obesity-Associated Fatty Liver Disease in Mice

Role of serotonin in fatty acid-induced non-alcoholic fatty liver disease in mice