American Journal of Physiology. Gastrointestinal and Liver Physiology

Enhanced free fatty acid (FFA) flux from adipose tissue (AT) to liver plays an important role in the development of non-alcoholic steatohepatitis (NASH) and alcohol-associated liver disease (AALD). We determined the effectiveness of nanoformulated superoxide dismutase 1 (Nano) in attenuating liver injury in a mouse model exhibiting a combination of NASH and AALD. Male C57BL6/J mice were fed a chow diet (CD) or a high fat diet (HF) for 10 wk followed by pair-feeding the Lieber-DeCarli control (control) or ethanol (ET) diet for 4 wk...

Hepatic stellate cells (HSCs) activation, characterized by development of a robust actin cytoskeleton and expression of abundant extracellular matrix (ECM) proteins such as type 1 collagen (COL.1), is a central cellular and molecular event in liver fibrosis. It has been demonstrated that HSCs express both myocardin and myocardin-related transcription factor-A (MRTF-A). However, the biological effects of myocardin and MRTF-A on HSC activation and liver fibrosis as well as the molecular mechanism under the process remain unclear...

Mixed acidic-alkaline refluxate is a major pathogenic factor in chronic esophagitis progressing into Barrett's esophagus (BE) but the involvement of epidermal growth factor (EGF), COX-2 and peroxisome proliferator-activated receptor gamma (PPARg) in BE has not been extensively studied. Rats surgically prepared with esophagogastroduodenal anastomosis (EGDA) with intact or removed salivary glands to deplete salivary EGF were treated either with: 1) vehicle, 2) EGF or pioglitazone with or without tyrphostin A46 or GW9662, respectively, 3) ranitidine or pantoprazole...

Background Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are common causes of chronic liver disease. The overlap between ALD and NAFLD suggests the existence of metabolic steatohepatitis. Development of in vivo models that reflect various aspects of human steatohepatitis is essential for drug discovery. We aimed to characterize several models of steatohepatitis (SH) and to investigate whether the pathology could be modulated. Methods Sprague Dawley rats were fed a high-fat diet (HFD) for 9 weeks, followed by either a high-fat, high cholesterol and cholate diet (HFC) or a HFC diet containing 13% trans-fat (HFC-TF)...

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease, characterized by excess fat accumulation (steatosis). Nonalcoholic steatohepatitis (NASH) develops in 15-20% of NAFLD patients, and frequently progresses to liver fibrosis and cirrhosis. We aimed to develop an ex vivo model of inflammation and fibrosis in steatotic murine precision-cut liver slices (PCLS). NASH was induced in C57Bl/6 mice using amylin and choline-deficient L-amino acid-defined (CDAA) diet. PCLS were prepared from steatohepatitic (sPCLS) and control (cPCLS) livers and cultured for 48h with LPS, TGFβ1 or elafibranor...

Hepatitis B virus (HBV)-related hepatocarcinogenesis is not necessarily associated with the liver fibrotic stage and is occasionally seen at early fibrotic stages. MicroRNAs (miRNAs) are essentially 18- to 22-nucleotide-long endogenous noncoding RNAs. Aberrant miRNA expression is a common feature of various human cancers. The aberrant expression of specific miRNAs has been shown in hepatocellular carcinoma (HCC) tissue compared to nontumor tissue. We thus examined targetable miRNAs as a potential new biomarker related to the high risk of HBV-related hepatocarcinogenesis, toward the prevention of cancer-related deaths...

Consumption of a high-fat diet has been associated with an increased risk of developing colorectal cancer (CRC). However, the effects of the interaction between dietary fat content and the aryl hydrocarbon receptor (AhR) on colorectal carcinogenesis remain unclear. Mainly known for its role in xenobiotic metabolism, AhR has been identified as an important regulator for maintaining intestinal epithelial homeostasis. Although previous research using whole-body AhR knockout mice has revealed an increased incidence of colon and cecal tumors, the unique role of AhR activity in intestinal epithelial cells (IECs) and modifying effects of fat content in the diet at different stages of sporadic CRC development has yet to be elucidated...

Bile acid receptors regulate the metabolic and immune functions of circulating enterohepatic bile acids. This process is disrupted by administration of parenteral nutrition (PN), which may induce progressive hepatic injury for unclear reasons, especially in the newborn, leading to PN-associated liver disease. To explore the role of bile acid signaling on neonatal hepatic function, we initially observed that TGR5-specific bile acids were negatively correlated with worsening clinical disease markers in the plasma of human newborns with prolonged PN exposure...

Intestinal-fatty acid binding protein (IFABP; FABP2) is a 15 kDa intracellular protein abundantly present in the cytosol of the small intestinal (SI) enterocyte. High fat (HF) feeding of IFABP-/- mice resulted in reduced weight gain and fat mass relative to wild-type (WT) mice. Here, we examined intestinal properties that may underlie the observed lean phenotype of high fat-fed IFABP-/- mice. No alterations in fecal lipid content were found, suggesting that the IFABP-/- mice are not malabsorbing dietary fat...

Longer colonic transit time and hard stools are associated with increased gut microbiota diversity. Here, we investigate to what extent quantitative measures of (segmental) colonic transit time were related to gut microbiota composition, microbial metabolites and gut-related parameters in a human cross-sectional study. Using radio-opaque markers, (segmental) colonic transit time (CTT) was measured in 48 lean/overweight participants with long colonic transit yet without constipation. Fecal microbiota composition was determined using 16S rRNA gene amplicon sequencing...

Gastric cancer (GC) is a most prevalent human cancer around the globe. In GC, Wnt signaling is deregulated, and receptor-like tyrosine kinase (RYK) co-receptors have been identified to interact with non-canonical Wnt ligand Wnt5a. We therefore aimed to evaluate the role of RYK in GC development and metastasis. GC tumor samples were collected from 250 GC patients. Expressions of RYK, as well as markers for the epithelial-mesenchymal transition (EMT) such as N-cadherin and E-cadherin were subjected to correlation analysis with clinicopathological features...

AIM: Acute kidney injury and hepatorenal syndrome (HRS) are frequent complications in patients with cirrhosis and ascites. First-line treatment is terlipressin, which reverses HRS in approximately 40% of patients but also lowers cardiac output (CO). We aimed to investigate whether reversing the cardio-suppressive effect of terlipressin with the β-adrenoceptor agonist dobutamine would increase CO and thereby the glomerular filtration rate (GFR). METHODS: We randomised twenty-five patients with cirrhosis, ascites and impaired renal function (2:2:1): Group A received terlipressin followed by add-on of dobutamine, Group B received dobutamine and terlipressin as monotherapies and Group C received placebo...

The interstitial cells of Cajal associated with the myenteric plexus (ICC-MP) are a network of coupled oscillators in the small intestine that generate rhythmic electrical phase waves leading to corresponding waves of contraction. Yet rhythmic action potentials and intercellular calcium waves have been recorded from c-kit mutant mice that lack the ICC-MP, suggesting that there may be a second pacemaker network. The gap junction blocker carbenoxolone induced a "pinstripe" motor pattern consisting of rhythmic "stripes" of contraction that appeared simultaneously across the intestine with a period of ~ 4 s...

BACKGROUND AND AIMS: In liver cirrhosis, oxidative stress plays a major role in promoting liver inflammation and fibrosis. Mitochondria dysregulation is responsible for excessive reactive oxygen species production. Therefore, in an experimental model of cirrhosis, we investigated the effect of mitochondria-targeted antioxidant mitoquinone. METHODS: Liver cirrhosis was induced in Spraque-Dawley rats by common bile duct ligation (CBDL). Mitoquinone (10 mg/kg/day, oral gavage) or vehicle were administered from 3rd to 28th day after CBDL, when animals were sacrificed and liver oxidative stress, inflammation, fibrosis, mitophagy were evaluated and in vivo and ex vivo hemodynamic studies were performed...

During intestinal inflammation, immature cells within the intestinal crypt are called upon to replenish lost epithelial cell populations, promote tissue regeneration and restore barrier integrity. Inflammatory mediators including TH 1/TH 17-associated cytokines influence tissue health and regenerative processes, yet how these cytokines directly influence the colon crypt epithelium, and whether the crypt remains responsive to these cytokines during active damage and repair, remains unclear. Here, using laser-capture microdissection and primary colon spheroid culture we show that the cytokine milieu regulates the ability of the colonic crypt epithelium to participate in pro-inflammatory signaling...

The mechanisms underlying electrical rhythmicity in smooth muscle of the proximal colon are incompletely understood. Our aim was to identify patterns of electrical rhythmicity in smooth muscle of the proximal region of isolated whole mouse colon and characterize their mechanisms of origin. Two independent extracellular recording electrodes were used to record the patterns of electrical activity in smooth muscle of the proximal region of whole isolated mouse colon. Cross correlation analysis was used to quantify spatial coordination of these electrical activities over increasing electrode separation distances...

Kras mutations are associated with pancreatic ductal adenocarcinoma (PDAC). Although tobacco smoking, pancreatitis, and obesity are known environmental risk factors for PDAC, contribution of moderate alcohol intake to PDAC remains elusive. In the present study, we tested whether a combination of risk factors or moderate alcohol intake induces PDAC development in mice. Control Pdx1 Cre and Pdx1 Cre ;LSL- Kras G12D mutant mice were fed a Western alcohol diet containing high levels of cholesterol and saturated fat, 3...

The effects of Brachyspira hyodysenteriae and Brachyspira hampsonii spirochetosis on Na+ transport was assessed in the colon to determine its contribution to diarrheal disease, in pigs following experimental infection. Electrogenic and electroneutral Na+ absorption was assessedin Ussing chambers by radiolabelled 22 Na flux and pharmacological inhibitory studies. Basal radiolabelled 22 Na flux experiments revealed that Jms was significantly impairedin B. hyodysenteriae and B. hampsonii diseased pigs. Inhibition of ENaC via amiloride did not significantly reduce electrogenic short-circuit current ( Isc ) in the proximal, apex, and distal colonic segments of diseased pigs over control pigs, suggesting that a loss of electroneutral Na+ absorption is responsible for diarrheal development...

The capacity of the colon to absorb microbially-produced amino acids (AAs) and the underlying mechanisms of AA transport are incompletely defined. We measured the profile of 16 fecal AAs along the rat ceco-colonic axis and compared unidirectional absorptive AA fluxes across mucosal tissues isolated from the rat jejunum, cecum, and proximal colon using an Ussing chamber approach in conjunction with 1 H-NMR and UPLC-MS chemical analyses. Passage of stool from cecum to mid-colon was associated with segment-specific changes in fecal AA composition and a decrease in total AA content...

Mechanosensitive signaling has emerged as a mechanism for the regulation of cholangiocyte transport and bile formation. The mechanical effect of fluid-flow, or shear, at the apical membrane of cholangiocytes regulates secretion through a process involving increases in [Ca2+]i and activation of Ca2+-activated Cl- channels. However, the initiating steps translating shear force to increases in [Ca2+]i are unknown. Transient Receptor Potential Vanilloid Member 4 (TRPV4), a non-selective cation channel present in the apical membrane of cholangiocytes, has been proposed as a potential mechanosensor...