Epithelial metabolism as a rheostat for intestinal inflammation and malignancy.

The gut epithelium protects the host from a potentially hostile environment while allowing nutrient uptake that is vital for the organism. To maintain this delicate task, the gut epithelium has evolved multilayered cellular functions ranging from mucus production to hormone release and orchestration of mucosal immunity. Here, we review the execution of intestinal epithelial metabolism in health and illustrate how perturbation of epithelial metabolism affects experimental gut inflammation and tumorigenesis. We also discuss the impact of environmental factors and host-microbe interactions on epithelial metabolism in the context of inflammatory bowel disease and colorectal cancer. Insights into epithelial metabolism hold promise to unravel mechanisms of organismal health that may be therapeutically exploited in humans in the future.

The pathophysiology of MASLD: an immunometabolic perspective.

INTRODUCTION: Metabolic-associated liver diseases have emerged pandemically across the globe and are clinically related to metabolic disorders such as obesity and type 2 diabetes. The new nomenclature and definition (i.e. metabolic dysfunction-associated steatotic liver disease - MASLD; metabolic dysfunction-associated steatohepatitis - MASH) reflect the nature of these complex systemic disorders, which are characterized by inflammation, gut dysbiosis and metabolic dysregulation. In this review, we summarize recent advantages in understanding the pathophysiology of MASLD, which we parallel to emerging therapeutic concepts. AREAS COVERED: We summarize the pathophysiologic concepts of MASLD and its transition to MASH and subsequent advanced sequelae of diseases. Furthermore, we highlight how dietary constituents, microbes and associated metabolites, metabolic perturbations, and immune dysregulation fuel lipotoxicity, hepatic inflammation, liver injury, insulin resistance, and systemic inflammation. Deciphering the intricate pathophysiologic processes that contribute to the development and progression of MASLD is essential to develop targeted therapeutic approaches to combat this escalating burden for health-care systems. EXPERT OPINION: The rapidly increasing prevalence of metabolic dysfunction-associated steatotic liver disease challenges health-care systems worldwide. Understanding pathophysiologic traits is crucial to improve the prevention and treatment of this disorder and to slow progression into advanced sequelae such as cirrhosis and hepatocellular carcinoma.

24-Norursodeoxycholic acid ameliorates experimental alcohol-related liver disease and activates hepatic PPARγ.

Background & Aims: Alcohol-related liver disease (ALD) is a global healthcare challenge with limited treatment options. 24-Norursodeoxycholic acid (NorUDCA) is a synthetic bile acid with anti-inflammatory properties in experimental and human cholestatic liver diseases. In the present study, we explored the efficacy of norUDCA in experimental ALD. Methods: NorUDCA was tested in a preventive and therapeutic setting in an experimental ALD model (Lieber-DeCarli diet enriched with ethanol). Liver disease was phenotypically evaluated using histology and biochemical methods, and anti-inflammatory properties and peroxisome proliferator-activated receptor gamma activation by norUDCA were evaluated in cellular model systems. Results: NorUDCA administration ameliorated ethanol-induced liver injury, reduced hepatocyte death, and reduced the expression of hepatic pro-inflammatory cytokines including tumour necrosis factor (Tnf), Il-1ß, Il-6, and Il-10. NorUDCA shifted hepatic macrophages towards an anti-inflammatory M2 phenotype. Further, norUDCA administration altered the composition of the intestinal microbiota, specifically increasing the abundance of Roseburia, Enterobacteriaceae, and Clostridum spp. In a therapeutic model, norUDCA also ameliorated ethanol-induced liver injury. Moreover, norUDCA suppressed lipopolysaccharide-induced IL-6 expression in human peripheral blood mononuclear cells and evoked peroxisome proliferator-activated receptor gamma activation. Conclusions: NorUDCA ameliorated experimental ALD, protected against hepatic inflammation, and affected gut microbial commensalism. NorUDCA could serve as a novel therapeutic agent in the future management of patients with ALD. Impact and implications: Alcohol-related liver disease is a global healthcare concern with limited treatment options. 24-Norursodeoxycholic acid (NorUDCA) is a modified bile acid, which was proven to be effective in human cholestatic liver diseases. In the present study, we found a protective effect of norUDCA in experimental alcoholic liver disease. For patients with ALD, norUDCA could be a potential new treatment option.

A gut bacterial signature in blood and liver tissue characterizes cirrhosis and hepatocellular carcinoma.

BACKGROUND: HCC is the leading cause of cancer in chronic liver disease. A growing body of experimental mouse models supports the notion that gut-resident and liver-resident microbes control hepatic immune responses and, thereby, crucially contribute to liver tumorigenesis. However, a comprehensive characterization of the intestinal microbiome in fueling the transition from chronic liver disease to HCC in humans is currently missing. METHODS: Here, we profiled the fecal, blood, and liver tissue microbiome of patients with HCC by 16S rRNA sequencing and compared profiles to nonmalignant cirrhotic and noncirrhotic NAFLD patients. RESULTS: We report a distinct bacterial profile, defined from 16S rRNA gene sequences, with reduced α-and ß-diversity in the feces of patients with HCC and cirrhosis compared to NAFLD. Patients with HCC and cirrhosis exhibited an increased proportion of fecal bacterial gene signatures in the blood and liver compared to NAFLD. Differential analysis of the relative abundance of bacterial genera identified an increased abundance of Ruminococcaceae and Bacteroidaceae in blood and liver tissue from both HCC and cirrhosis patients compared to NAFLD. Fecal samples from cirrhosis and HCC patients both showed a reduced abundance for several taxa, including short-chain fatty acid-producing genera, such as Blautia and Agathobacter. Using paired 16S rRNA and transcriptome sequencing, we identified a direct association between gut bacterial genus abundance and host transcriptome response within the liver tissue. CONCLUSIONS: Our study indicates perturbations of the intestinal and liver-resident microbiome as a critical determinant of patients with cirrhosis and HCC.

Non-alcoholic fatty liver disease: pathophysiological concepts and treatment options.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is continually increasing due to the global obesity epidemic. NAFLD comprises a systemic metabolic disease accompanied frequently by insulin resistance and hepatic and systemic inflammation. Whereas simple hepatic steatosis is the most common disease manifestation, a more progressive disease course characterized by liver fibrosis and inflammation (i.e. non-alcoholic steatohepatitis) is present in 10-20% of affected individuals. NAFLD furthermore progresses in a substantial number of patients towards liver cirrhosis and hepatocellular carcinoma. Whereas this disease now affects almost 25% of the world's population and is mainly observed in obesity and type 2 diabetes, NAFLD also affects lean individuals. Pathophysiology involves lipotoxicity, hepatic immune disturbances accompanied by hepatic insulin resistance, a gut dysbiosis, and commonly hepatic and systemic insulin resistance defining this disorder a prototypic systemic metabolic disorder. Not surprisingly many affected patients have other disease manifestations, and indeed cardiovascular disease, chronic kidney disease, and extrahepatic malignancies are all contributing substantially to patient outcome. Weight loss and lifestyle change reflect the cornerstone of treatment, and several medical treatment options are currently under investigation. The most promising treatment strategies include glucagon-like peptide 1 receptor antagonists, sodium-glucose transporter 2 inhibitors, Fibroblast Growth Factor analogues, Farnesoid X receptor agonists, and peroxisome proliferator-activated receptor agonists. Here, we review epidemiology, pathophysiology, and therapeutic options for NAFLD.

Nonalcoholic Fatty Liver Disease and the Intestinal Microbiome: An Inseparable Link.

Nonalcoholic fatty liver disease (NAFLD) particularly affects patients with type 2 diabetes and obesity. The incidence of NAFLD has increased significantly over the last decades and is now pandemically across the globe. It is a complex systemic disease comprising hepatic lipid accumulation, inflammation, lipotoxicity, gut dysbiosis, and insulin resistance as main features and with the potential to progress to cirrhosis and hepatocellular carcinoma (HCC). In numerous animal and human studies the gut microbiota plays a key role in the pathogenesis of NAFLD, NAFLD-cirrhosis and NAFLD-associated HCC. Lipotoxicity is the driver of inflammation, insulin resistance, and liver injury. Likewise, western diet, obesity, and metabolic disorders may alter the gut microbiota, which activates innate and adaptive immune responses and fuels hereby hepatic and systemic inflammation. Indigestible carbohydrates are fermented by the gut microbiota to produce important metabolites, such as short-chain fatty acids and succinate. Numerous animal and human studies suggested a pivotal role of these metabolites in the progression of NAFLD and its comorbidities. Though, modification of the gut microbiota and/or the metabolites could even be beneficial in patients with NAFLD, NAFLD-cirrhosis, and NAFLD-associated HCC. In this review we collect the evidence that exogenous and endogenous hits drive liver injury in NAFLD and propel liver fibrosis and the progressing to advanced disease stages. NAFLD can be seen as the product of a complex interplay between gut microbiota, the immune response and metabolism. Thus, the challenge will be to understand its pathogenesis and to develop new therapeutic strategies.

The metabolic nature of inflammatory bowel diseases.

Crohn's disease and ulcerative colitis, phenotypically comprising a spectrum of inflammatory bowel diseases (IBDs), spread globally during the westernization of lifestyle and dietary habits over the past few decades. Here, we review experimental and clinical evidence for the metabolic nature of gut inflammation in IBD and delineate distinct parallels to the inflammatory state in metabolic diseases. Experimental evidence indicates that excessive intake of specific macronutrients in a Western diet fuels an inflammatory response in the gut by exploiting sensors of innate immunity and perturbation of gut microbial metabolism. Genetic IBD risk partly affects metabolism and stress signalling of innate immunity, and immunometabolism controls susceptibility to gut inflammation. Epidemiological and clinical studies indicate that specific nutrients in the Western diet pose a risk for the development of IBD and a poor disease course. Translational studies in IBD indicate perturbation of energy metabolism in immune cells and perturbation of gut microbial metabolism, which can be shaped by diet. In turn, dietary restriction by exclusive enteral nutrition induces remission in patients with IBD. Collectively, these studies support a metabolic underpinning of gut inflammation in IBD as described for metabolic inflammation in obesity and related disorders.

PUFA-Induced Metabolic Enteritis as a Fuel for Crohn's Disease.

BACKGROUND & AIMS: Crohn's disease (CD) globally emerges with Westernization of lifestyle and nutritional habits. However, a specific dietary constituent that comprehensively evokes gut inflammation in human inflammatory bowel diseases remains elusive. We aimed to delineate how increased intake of polyunsaturated fatty acids (PUFAs) in a Western diet, known to impart risk for developing CD, affects gut inflammation and disease course. We hypothesized that the unfolded protein response and antioxidative activity of glutathione peroxidase 4 (GPX4), which are compromised in human CD epithelium, compensates for metabolic perturbation evoked by dietary PUFAs. METHODS: We phenotyped and mechanistically dissected enteritis evoked by a PUFA-enriched Western diet in 2 mouse models exhibiting endoplasmic reticulum (ER) stress consequent to intestinal epithelial cell (IEC)-specific deletion of X-box binding protein 1 (Xbp1) or Gpx4. We translated the findings to human CD epithelial organoids and correlated PUFA intake, as estimated by a dietary questionnaire or stool metabolomics, with clinical disease course in 2 independent CD cohorts. RESULTS: PUFA excess in a Western diet potently induced ER stress, driving enteritis in Xbp1-/-IEC and Gpx4+/-IEC mice. ω-3 and ω-6 PUFAs activated the epithelial endoplasmic reticulum sensor inositol-requiring enzyme 1α (IRE1α) by toll-like receptor 2 (TLR2) sensing of oxidation-specific epitopes. TLR2-controlled IRE1α activity governed PUFA-induced chemokine production and enteritis. In active human CD, ω-3 and ω-6 PUFAs instigated epithelial chemokine expression, and patients displayed a compatible inflammatory stress signature in the serum. Estimated PUFA intake correlated with clinical and biochemical disease activity in a cohort of 160 CD patients, which was similarly demonstrable in an independent metabolomic stool analysis from 199 CD patients. CONCLUSIONS: We provide evidence for the concept of PUFA-induced metabolic gut inflammation which may worsen the course of human CD. Our findings provide a basis for targeted nutritional therapy.

Hepatic Meteorin-like and Krüppel-like Factor 3 are Associated with Weight Loss and Liver Injury.

OBJECTIVE: Laparoscopic adjustable gastric banding (LAGB) was found to be effective in reducing body weight and improving insulin resistance in patients with obesity and non-alcoholic fatty liver disease (NAFLD). The adipokine/myokine meteorin-like (METNRL) is an important regulator of whole-body energy expenditure. Krüppel-like factor 3 (KLF3), a regulator of METRNL expression in eosinophils, inhibits the beiging of adipose tissue in mice and therefore regulates adipose tissue development. METHODS: Thirty-three obese patients undergoing LAGB were included in the study. The hepatic and adipose tissue expression of METNRL and KLF3 was determined before (t0) and 6 months after (t6) LABG. The human liver cancer cell line (HepG2) was stimulated with cytokines and fatty acids and METNRL and KLF3 expressions were analyzed. RESULTS: LAGB-associated weight loss was correlated with decreased hepatic METNRL expression. The expression of METNRL and KLF3 in hepatic-and adipose tissues correlated before and after LAGB. Individuals with augmented LAGB-induced weight loss (>20 kg) showed lower hepatic METNRL and KLF3 expression before and after LAGB than patients with <20 kg weight loss. METNRL and KLF3 levels were higher in patients with higher NAFLD activity scores. HepG2 stimulation with interleukin-1ß, tumor necrosis factor-α, palmitic acid but not interleukin-6, oleic acid, or lipopolysaccharide, induced the expression of one or both investigated adipokines. CONCLUSIONS: The novel description of METRNL and KLF3 as hepatokines could pave the way to target their production and/or signaling in obesity, NAFLD, and related disorders. Both proteins may act as possible biomarkers to estimate weight loss after bariatric surgery.

Increased Fecal Neopterin Parallels Gastrointestinal Symptoms in COVID-19.

INTRODUCTION: Coronavirus disease (COVID-19) has spread from Wuhan, China, and become a worldwide pandemic. Most patients display respiratory symptoms but up to 50% report gastrointestinal symptoms. Neopterin is a surrogate marker for viral inflammation, and its production by macrophages is driven by interferon-γ. METHODS: We measured fecal neopterin in 37 hospitalized COVID-19 patients not requiring intensive care measures and 22 healthy controls. RESULTS: Fecal neopterin was elevated in stool samples from COVID-19 patients compared with that in samples from healthy controls. Especially, patients reporting gastrointestinal symptoms exhibited increased fecal neopterin values. DISCUSSION: COVID-19 is associated with an inflammatory immune response in the gastrointestinal tract.

Systemic inflammation as fuel for acute liver injury in COVID-19.

BACKGROUND: A cytokine storm conceivably contributes to manifestations of corona virus disease (COVID-19). Inflammatory cytokines such as interleukin-6 (IL-6) cause acute liver injury while serum detectability indicates systemic inflammation. AIMS: We explored a link between systemic IL-6, related acute phase proteins and liver injury in hospitalized COVID-19 patients. METHODS: 655 patients with suspected COVID-19 were screened in the emergency department at the University Hospital of Innsbruck, Austria, between February and April 2020. 96 patients (∼15%) were hospitalized with COVID-19. 15 patients required intensive-care treatment (ICT). Plasma aminotransferases, alkaline phosphatase, bilirubin, and gamma glutamyl transferase, as well as IL-6, C-reactive protein (CRP), ferritin and lactate dehydrogenase (LDH) were determined by standard clinical assays. RESULTS: Of all hospitalized COVID-19 patients, 41 (42%) showed elevated aspartate aminotransferase (AST) concentration. COVID-19 patients with elevated AST exhibited significantly higher IL-6 (p < 0.001), ferritin (p < 0.001), LDH (p < 0.001) and CRP (p < 0.05) serum concentrations compared to patients with normal AST. Liver injury correlated with systemic IL-6 (p < 0.001), CRP (p < 0.001), ferritin (p < 0.001) and LDH (p < 0.001) concentration. In COVID-19 patients requiring ICT, correlations were more pronounced. CONCLUSION: Systemic inflammation could be a fuel for hepatic injury in COVID-19.

Gastric banding-associated weight loss diminishes hepatic Tsukushi expression.

Obesity has emerged as a substantial global healthcare issue that is frequently associated with insulin resistance and non-alcoholic fatty liver disease (NAFLD). Tsukushi (TSK), a liver-derived molecule, was recently identified as a major driver of NAFLD. Laparoscopic adjustable gastric banding (LAGB) has proven effective in reducing body weight and improving NAFLD. We therefore aimed to investigate the relation between LAGB-induced weight loss and TSK expression. Twenty-six obese patients undergoing LAGB were included in the study and metabolic parameters were assessed before (t0) and six months after LAGB (t6). The expression of TSK in liver and subcutaneous adipose tissue (AT) specimens was determined at both time points. To unravel regulatory mechanisms of TSK expression, human peripheral blood mononuclear cells (PBMCs) were stimulated with pro-inflammatory cytokines and TSK mRNA levels were analyzed by quantitative polymerase chain reaction. LAGB induced pronounced weight loss which was paralleled by amelioration of metabolic disturbances and histologically defined NAFLD. While hepatic TSK expression was markedly decreased after LAGB, adipose tissue TSK expression remained comparable to baseline. The decline in hepatic TSK expression after LAGB positively correlated with weight loss and the reduction in BMI, and negatively correlated with NAFLD activity score (NAS). In human PBMCs, pro-inflammatory cytokines such as IL-1ß and TNFα induced the expression of TSK. In conclusion, LAGB-induced weight loss reduces hepatic TSK expression. Inhibiting TSK might represent a promising target for treating NAFLD in the future.

Dietary lipids fuel GPX4-restricted enteritis resembling Crohn's disease.

The increased incidence of inflammatory bowel disease (IBD) has become a global phenomenon that could be related to adoption of a Western life-style. Westernization of dietary habits is partly characterized by enrichment with the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA), which entails risk for developing IBD. Glutathione peroxidase 4 (GPX4) protects against lipid peroxidation (LPO) and cell death termed ferroptosis. We report that small intestinal epithelial cells (IECs) in Crohn's disease (CD) exhibit impaired GPX4 activity and signs of LPO. PUFAs and specifically AA trigger a cytokine response of IECs which is restricted by GPX4. While GPX4 does not control AA metabolism, cytokine production is governed by similar mechanisms as ferroptosis. A PUFA-enriched Western diet triggers focal granuloma-like neutrophilic enteritis in mice that lack one allele of Gpx4 in IECs. Our study identifies dietary PUFAs as a trigger of GPX4-restricted mucosal inflammation phenocopying aspects of human CD.

Targeting NAD immunometabolism limits severe graft-versus-host disease and has potent antileukemic activity.

Acute graft-versus-host disease (aGVHD) and tumor relapse remain major complications after allogeneic hematopoietic stem cell transplantation. Alloreactive T cells and cancer cells share a similar metabolic phenotype to meet the bioenergetic demands necessary for cellular proliferation and effector functions. Nicotinamide adenine dinucleotide (NAD) is an essential co-factor in energy metabolism and is constantly replenished by nicotinamide phosphoribosyl-transferase (Nampt), the rate-limiting enzyme in the NAD salvage pathway. Here we show, that Nampt blockage strongly ameliorates aGVHD and limits leukemic expansion. Nampt was highly elevated in serum of patients with gastrointestinal GVHD and was particularly abundant in human and mouse intestinal T cells. Therapeutic application of the Nampt small-molecule inhibitor, Fk866, strongly attenuated experimental GVHD and caused NAD depletion in T-cell subsets, which displayed differential susceptibility to NAD shortage. Fk866 robustly inhibited expansion of alloreactive but not memory T cells and promoted FoxP3-mediated lineage stability in regulatory T cells. Furthermore, Fk866 strongly reduced the tumor burden in mouse leukemia and graft-versus-leukemia models. Ex vivo studies using lymphocytes from GVHD patients demonstrated potent antiproliferative properties of Fk866, suggesting potential clinical utility. Thus, targeting NAD immunometabolism represents a novel approach to selectively inhibit alloreactive T cells during aGVHD with additional antileukemic efficacy.

Gut Dysfunction and Non-alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) has emerged as one of the leading liver diseases worldwide. NAFLD is characterized by hepatic steatosis and may progress to an inflammatory condition termed non-alcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma. It became evident in the last years that NAFLD pathophysiology is complex and involves diverse immunological and metabolic pathways. An association between intestinal signals (e.g., derived from the gut microbiota) and the development of obesity and its metabolic consequences such as NAFLD are increasingly recognized. Pre-clinical studies have shown that germ-free mice are protected against obesity and hepatic steatosis. Several human studies from the past years have demonstrated that NAFLD contains a disease-specific gut microbiome signature. Controlled studies propose that certain bacteria with rather pro-inflammatory features such as Proteobacteria or Escherichia coli are dominantly present in these patients. In contrast, rather protective bacteria such as Faecalibacterium prausnitzii are decreased in NAFLD patients. Furthermore, various bacterial metabolites and microbiota-generated secondary bile acids are involved in NAFLD-associated metabolic dysfunction. Although these findings are exciting, research currently lack evidence that interference at the level of the gut microbiome is beneficial for these diseases. Further preclinical and clinical studies are needed to advance this aspect of NAFLD research and to support the notion that the intestinal microbiota is indeed of major relevance in this disorder.

Pancreas-Microbiota Cross Talk in Health and Disease.

The pancreas controls metabolism through endocrine and exocrine functions. Pancreatic diseases comprise a spectrum of mild to life-threatening conditions, including acute and chronic pancreatitis, diabetes, and pancreatic cancer, which affect endocrine and exocrine pancreatic function and impose a substantial disease burden on individuals. Increasing experimental evidence demonstrates that the intestinal microbiota has an important impact on pancreatic function and diseases. This influence may be conferred by bacterial metabolites, such as short-chain fatty acids, or the modulation of immune responses. In turn, pancreatic factors, such as the excretion of antimicrobials, might have a substantial impact on the composition and functional properties of the gut microbiota. Here, we summarize experimental and clinical approaches used to untie the intricate pancreas-microbiota cross talk. Future advances will allow clinicians to manipulate the intestinal microbiota and guide patient management in pancreatic diseases.

Weight Loss Induced by Bariatric Surgery Restricts Hepatic GDF15 Expression.

Introduction: Obesity and related nonalcoholic fatty liver disease (NAFLD) are an emerging health care issue that imposes substantial morbidity to individuals. Growth and differentiation factor 15 (GDF15) limits food uptake, body weight, and energy balance by modulation of GDNF-family receptor α-like (GFRAL) signalling in the hindbrain. However, the regulation of GDF15 expression in obesity and NAFLD is incompletely understood. We sought to define the impact of weight loss achieved by laparoscopic adjustable gastric banding (LAGB) on hepatic and adipose GDF15 expression in a cohort of severely obese patients. Methods: We analysed GDF15 expression of liver and subcutaneous adipose tissue before and 6 months after LAGB in severely obese patients undergoing LAGB by quantitative real-time PCR. To assess the role of inflammation on GDF15 expression, we analysed Hep G2 hepatocytes stimulated with cytokines such as IL-1ß, TNFα, IL-6, LPS, or cellular stressors such as tunicamycin. Results: GDF15 expression was mostly confined to the liver compared to adipose tissue in severely obese patients. Weight loss induced by LAGB was associated with reduced hepatic (but not adipose tissue) expression of GDF15. Stimulation with IL-1ß or tunicamycin induced hepatic GDF15 expression in hepatocytes. In line with this, hepatic GDF15 expression directly correlated with IL-1ß expression and steatosis severity in NAFLD. These data demonstrated that amelioration of metabolic inflammation and weight loss reduced hepatic GDF15 expression. Conclusion: Based on recent mechanistic findings, our data suggest that hepatic GDF15 may serve as a negative feedback mechanism to control energy balance in NAFLD.

Adipose type I interferon signalling protects against metabolic dysfunction.

OBJECTIVE: Low-grade chronic inflammation emerges as a potent driver of insulin resistance and glucose dysregulation in obesity and associated non-alcoholic fatty liver disease (NAFLD). The liver, subcutaneous fat and the immune system participate in disturbances of metabolism. Type I interferon (IFN) signalling initiated by innate and adaptive immunity modulates inflammatory responses consequent to infection. However, little is known about the role of type I IFN signalling in metabolic diseases and the development of NAFLD. DESIGN: We determined the impact of type I IFN signalling by tissue-specific deletion of interferon (α and ß) receptor 1 (Ifnar1) in hepatocytes (Ifnar1Δhep ), adipocytes (Ifnar1Δat ), intestinal epithelial cells (Ifnar1ΔIEC ) or myelocytes (Ifnar1Δmyel ) on glucose metabolism, obesity and hepatic disease in mice exposed to a high-fat or methionine-choline-deficient (MCD) diet. Furthermore, we investigated the expression of type I IFN-regulated genes in patients with obesity undergoing laparoscopic adjustable gastric banding (LAGB). RESULTS: Long chain fatty acids induce type I IFN responses in murine hepatocytes and macrophages and exposure to a high-fat diet elicited type I IFN-regulated gene expression in the liver of wild-type mice. Hepatocyte-specific, but not adipose tissue-specific deletion of Ifnar1 worsened steatosis and inflammation induced by the MCD diet. In contrast, adipose-specific, but not hepatocyte-specific deletion of Ifnar1 deteriorated metabolic dysregulation induced by a high-fat diet, indicated by increased weight gain, insulin resistance and an impaired glucose tolerance. Abrogated type I IFN signalling in myeloid or intestinal epithelial cells did not modulate susceptibility to metabolic or hepatic disease. Improved metabolic control in patients with obesity after LAGB was associated with increased expression of type I IFN-regulated genes in subcutaneous adipose tissue and liver. CONCLUSIONS: Our study implicates a role for adipose and hepatocyte type I IFN signalling in diet-induced metabolic dysregulation and hepatic disease. Further studies on type I IFN signalling in metabolic diseases are warranted.

Adipokines and Non-Alcoholic Fatty Liver Disease: Multiple Interactions.

Accumulating evidence links obesity with low-grade inflammation which may originate from adipose tissue that secretes a plethora of pro- and anti-inflammatory cytokines termed adipokines. Adiponectin and leptin have evolved as crucial signals in many obesity-related pathologies including non-alcoholic fatty liver disease (NAFLD). Whereas adiponectin deficiency might be critically involved in the pro-inflammatory state associated with obesity and related disorders, overproduction of leptin, a rather pro-inflammatory mediator, is considered of equal relevance. An imbalanced adipokine profile in obesity consecutively contributes to metabolic inflammation in NAFLD, which is associated with a substantial risk for developing hepatocellular carcinoma (HCC) also in the non-cirrhotic stage of disease. Both adiponectin and leptin have been related to liver tumorigenesis especially in preclinical models. This review covers recent advances in our understanding of some adipokines in NAFLD and associated HCC.

Lipocalin 2 drives neutrophilic inflammation in alcoholic liver disease.

BACKGROUND & AIMS: Alcoholic steatohepatitis (ASH) is characterised by neutrophil infiltration that contributes to hepatic injury and disease. Lipocalin-2 (LCN2) was originally identified as siderophore binding peptide in neutrophils, which exerted tissue protective effects in several disease models. Here we investigate the role of LCN2 in the pathogenesis of alcohol-induced liver injury. METHODS: We compared hepatic LCN2 expression in ASH patients, alcoholic cirrhosis patients without evidence of ASH and patients with non-alcoholic fatty liver disease (NAFLD; i.e. simple steatosis). To mechanistically dissect LCN2 function in alcohol-induced liver injury, we subjected wild-type (WT) and Lcn2-deficient (Lcn2(-/-)) mice to the Lieber-DeCarli diet containing 5% ethanol (EtOH) or isocaloric maltose. Adoptive transfer experiments were performed to track neutrophil migration. Furthermore, we tested the effect of antibody-mediated LCN2 neutralisation in an acute model of ethanol-induced hepatic injury. RESULTS: Patients with ASH exhibited increased hepatic LCN2 immunoreactivity compared to patients with alcoholic cirrhosis or simple steatosis, which mainly localised to neutrophils. Similarly, ethanol-fed mice exhibited increased LCN2 expression that mainly localised to leukocytes and especially neutrophils. Lcn2(-/-) mice were protected from alcoholic liver disease (ALD) as demonstrated by reduced neutrophil infiltration, liver injury and hepatic steatosis compared to WT controls. Adoptive transfers revealed that neutrophil-derived LCN2 critically determines hepatic neutrophil immigration and persistence during chronic alcohol exposure. Antibody-mediated neutralisation of LCN2 protected from hepatic injury and neutrophilic infiltration after acute alcohol challenge. CONCLUSIONS: LCN2 drives ethanol-induced neutrophilic inflammation and propagates the development of ALD. Despite a critical role for LCN2 in immunity and infection, pharmacological neutralisation of LCN2 might be of promise in ALD.