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Chen, Xue; Acquaah-Mensah, George K.; Denning, Krista L.; Peterson, Jonathan M.; Wang, Kesheng; Denvir, James; Hong, Feng; Cederbaum, Arthur I.; Lu, Yongke
doi: 10.1152/ajpgi.00213.2020pmid: 32877213
Obesity is linked to non-alcoholic steatohepatitis. PPARα regulates lipid metabolism. CYP2A5 is a potential antioxidant and CYP2A5 induction by ethanol is CYP2E1-dependent. High fat diet (HFD)-induced obesity and steatosis are more severe in CYP2A5 knockout (cyp2a5-/-) mice than in wild-type mice although PPARα is elevated in cyp2a5-/- mice. To examine why the up-regulated PPARα failed to prevent the enhanced steatosis in cyp2a5-/- mice, we abrogate the up-regulated PPARα in cyp2a5-/- mice by cross-breeding cyp2a5-/- mice with PPARα knockout (pparα-/-) mice to create pparα-/-/cyp2a5-/- mice. The pparα-/-/cyp2a5-/- mice, pparα-/- mice, and cyp2a5-/- mice were fed HFD to induce steatosis. After HFD feeding, more severe steatosis was developed in pparα-/-/cyp2a5-/- mice than in pparα-/- mice and cyp2a5-/- mice. The pparα-/-/cyp2a5-/- mice and pparα-/-mice exhibited comparable and impaired lipid metabolism. Elevated serum ALT and liver IL-1β, liver inflammatory cell infiltration, foci of hepatocellular ballooning were observed in pparα-/-/cyp2a5-/- mice but not in pparα-/- mice and cyp2a5-/- mice. In pparα-/-/cyp2a5-/- mice, although redox sensitive transcription factor Nrf2 and its target antioxidant genes were upregulated as a compensation, thioredoxin was suppressed, and phosphorylation of JNK and formation of nitrotyrosine adduct were increased. liver glutathione was decreased, and lipid peroxidation was increased. Interestingly, inflammation and fibrosis were all observed within the clusters of lipid droplets, and these lipid droplet clusters were all located inside the area with CYP2E1 positive staining. These results suggest that HFD-induced fibrosis in pparα-/-/cyp2a5-/- mice is associated with steatosis, and CYP2A5 interacts with PPARα to participate in regulating steatohepatitis-associated fibrosis.
doi: 10.1152/ajpgi.00042.2020pmid: 32755375
Evidence exists reporting that microRNA-1228 (miR-1228) functions as an oncomiR in hepatocellular carcinoma (HCC). This study aimed to identify whether extracellular vesicles (EVs) could transfer miR-1228-3p into HCC cells and probe the mechanisms underlying its roles in tumorigenesis. Normal fibroblasts (NFs) and cancer-associated fibroblasts (CAFs) were isolated from HCC patients, followed by isolation of EVs. The relationship between miR-1228-3p and placenta special gene 8 (PLAC8) was predicted by computer-based analysis and subsequently verified by dual-luciferase reporter gene assay. Cellular behaviors and drug resistance to Sorafenib were evaluated in the HCC cells in a co-culture system with NFs or CAFs containing aberrantly expressed miR-1228-3p. An orthotopic HCC model in nude mice was developed for demonstrating our findings in vivo. CAFs-derived EVs could promote the proliferative, migrating, invading potentials of HCC cells and enhance the resistance to Sorafenib in vitro, and likewise in vivo. Overexpressed miR-1228-3p enhanced the malignant behaviors of HCC cells and activated the PI3K/AKT signaling pathway via downregulation of PLAC8, which was confirmed as a target gene of miR-1228-3p. Moreover, the transfer of miR-1228-3p from CAFs-derived EVs into HCC cells contributed to chemoresistance of HCC cells, while overexpressed PLAC8 could partially reverse the effects of miR-1228-3p. Taken together, EV-delivered miR-1228-3p from CAFs promoted the chemoresistance of HCC cells, providing an insight into developing novel therapeutic strategies against HCC.
Ryou, Marvin; Stylopoulos, Nicholas
doi: 10.1152/ajpgi.00135.2020pmid: 32877219
Portal and hepatic circulation can now be safely accessed using endoscopic ultrasound (EUS). EUS-guided needle access of the portal vein is performed clinically at select tertiary centers for measurement of portal pressure gradients in patients with chronic liver disease and sampling of portal venous thrombus to diagnose malignancy. We propose that this novel clinical technique can be applied in research studies to allow blood collection from and profiling of portal and hepatic circulation. In this technical report, we present and highlight the technical aspects, feasibility and safety of EUS - guided portal venous blood collection. As a proof of the concept and the utility of this technique in metabolic research and biomarker assessment and discovery, we present a pilot metabolite profiling study of portal venous blood in a small cohort of patients with cirrhosis and a comparison to a group without cirrhosis. Despite the very small diameter of the endoscopic needle used for the blood collection, the portal samples have the same quality as those collected from systemic circulation, and they can be used for the same downstream applications. Finally, we propose an analytical workflow to screen for promising metabolites that could qualify for further studies to determine their utility as sensitive, early, candidate biomarkers of hepatic fibrosis, portal shunt and hypertension. We hope that this report could stimulate and facilitate the widespread use of EUS-guided techniques for the profiling of portal circulation, which could potentially open a new field of scientific inquiry.
Foong, Jaime P. P.; Hung, Lin Y.; Poon, Sabrina; Savidge, Tor C.; Bornstein, Joel C.
doi: 10.1152/ajpgi.00288.2020pmid: 32902314
Recent studies on humans and their key experimental model, the mouse, have begun to uncover the importance of gastrointestinal (GI) microbiota and Enteric Nervous System (ENS) interactions during developmental windows spanning from conception to adolescence. Disruptions in GI microbiota and ENS during these windows by environmental factors particularly antibiotic exposure have been linked to increased susceptibility of the host to several diseases. Mouse models have provided new insights to potential signalling factors between the microbiota and ENS. We review very recent work on maturation of GI microbiota and ENS during three key developmental windows: embryogenesis, early postnatal and post-weaning periods. We discuss advances in understanding of interactions between the two systems and highlight research avenues for future studies.
Bhattarai, Yogesh; Kashyap, Purna C.
doi: 10.1152/ajpgi.00058.2020pmid: 32877215
Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by motor and gastrointestinal (GI) deficits. Despite its prevalence, the pathophysiology of PD is not well understood. Recent studies highlight the role of gut microbiota in neurological disorders. In this review, we summarize the potential role of gut microbiota in the pathophysiology of PD. We first describe how gut microbiota can be influenced by factors predisposing individuals to PD, such as environmental toxins, aging, and host genetics. We then highlight the effect of gut microbiota on mechanisms implicated in the pathophysiology of PD, including disrupted microbiota gut brain axis (GBA), barrier dysfunction, and immune dysfunction. It is too early to connect the dots between gut microbiota and PD to establish causation, and experiments focused on investigating interrelationship between gut microbiota and associated metabolites on GBA, barrier dysfunction, and immune activation will be crucial to fill in the gaps.
doi: 10.1152/ajpgi.00152.2020pmid: 32902316
Circadian rhythms are biological systems that synchronize cellular circadian oscillators with the organism's daily feeding-fasting or rest-activity cycles in mammals. Circadian rhythms regulate nutrient absorption and utilization at the cellular level, and are closely related to obesity and metabolic disorders. Bile acids are important modulators that facilitate nutrient absorption and regulate energy metabolism. Here, we provide an overview of the current connections and future perspectives between the circadian clock and bile acids metabolism as well as related metabolic diseases. Feeding and fasting cycles influence bile acid pool size and composition, and bile acid signaling can respond to acute lipid and glucose utilization and mediate energy balance. Disruption of circadian rhythms, such as shift work, irregular diet, and gene mutations can contribute to altered bile acid metabolism and heighten obesity risk. High-fat diets, alcohol and gene mutations related to bile acid signaling result in desynchronized circadian rhythms. Gut microbiome also plays a role in connecting circadian rhythms with bile acids metabolism. The underlying mechanism of how circadian rhythms interact with bile acids metabolism has not been fully explored. Sustaining bile acids homeostasis based on circadian rhythms may be potential therapies to alleviate metabolic disturbance.
Tsuji, Kojun; Tsujimura, Takanori; Sakai, Shogo; Suzuki, Taku; Yoshihara, Midori; Nagoya, Kouta; Magara, Jin; Satoh, Yoshihide; Inoue, Makoto
doi: 10.1152/ajpgi.00233.2020pmid: 32878469
Capsaicin powerfully evokes the swallowing reflex and is a known therapeutic agent for improving dysphagia and preventing aspiration pneumonia. However, the role of capsaicin-sensitive nerves in the initiation of swallowing evoked by various natural stimuli remains unclear. To explore this question, we blocked laryngeal capsaicin-sensitive nerves following the co-application of QX-314 and capsaicin (QX/Cap), and investigated the effects on swallowing evoked by mechanical and chemical stimulation in anesthetized rats. Swallows were evoked by capsaicin, carbonated water (CW), distilled water (DW), and punctate mechanical stimulation using von Frey filaments applied topically to the larynx. Swallows were documented by recording electromyographic activation of the suprahyoid and thyrohyoid muscles. The initiation of swallowing by capsaicin was strongly suppressed at 5 minutes following QX/Cap treatment and facilitated in a time-dependent manner. CW-evoked swallows at 5 min following QX/Cap treatment were significantly diminished compared with before and 30 min after treatment. In contrast, DW-evoked and mechanically evoked swallows were unchanged by QX/Cap treatment. Furthermore, CW-evoked swallows were virtually abolished by transection of the superior laryngeal nerves and significantly decreased by the topical application of ASIC3 inhibitor APET×2, but they were not affected by the non-selective TRP channel inhibitor ruthenium red or the ASIC1 inhibitor mambalgin-1. Taken together, we speculate that capsaicin-sensitive nerves play an important role in the initiation of CW-evoked swallows.
Komara, Nicole L.; Paragomi, Pedram; Greer, Phil J.; Wilson, Anette S.; Breze, Cameron; Papachristou, Georgios I.; Whitcomb, David C.
doi: 10.1152/ajpgi.00285.2020pmid: 32877220
Background and Aims: Severe acute pancreatitis (SAP) includes persistent systemic inflammation (SIRS) and multi-organ failure (MOF). The mechanism of transition from SIRS to MOF is unclear. We developed a fluid compartment model and used clinical data to test predictions. Methods. The model includes vascular, interstitial and "third space" compartments with variable permeability of plasma proteins at the capillaries. Consented patients from UPMC Presbyterian Hospital were studied. Pre-admission and daily hematocrit (HCT), blood urea nitrogen (BUN), creatine (Cr), albumin (Alb) and total protein (TP) were collected, and non-albumin plasma protein (NAPP=TP-Alb) was calculated. Subjects served as their own controls for trajectory analysis. Results: Of 57 SAP subjects 18 developing MOF (5 died) and 39 non-MOF (0 died). Compared to pre-admission levels, admission HCT increased in MOF +5.00 [3.70, 8.70] versus non-MOF -0.10 [-1.55, 1.40] (p<0.002) with HCT >+3 distinguishing MOF from non-MOF (OR 17.7, p=0.014). Preadmission Alb fell faster in MOF than non-MOF (p<0.01). By day 2 TP and NAPP dropped in MOF but not non-MOF (p<0.001). BUN and Cr levels increased in MOF (p=0.001) but BUN/Cr ratios remained constant. Pancreatic necrosis was more common in MOF (56%) than non-MOF (23%). Conclusions: Changing capillary permeability to allow loss of NAPP in this model predicts loss of plasma oncotic pressure and reduced vascular volume, hypotension with pre-renal azotemia and acute kidney dysfunction, pancreas necrosis, and pulmonary edema from capillary leak in the lung with acute respiratory distress syndrome. Sequential biomarker analysis in humans with or without MOF is consistent with this model.
doi: 10.1152/ajpgi.00161.2020pmid: 32683951
Increasing evidence have demonstrated that methyltransferase-like 3 (METTL3) plays an oncogenic role in the development of human hepatocellular carcinoma (HCC), however, the underlying mechanisms still remain largely unexplored. We investigated the effect of METTL3/microRNA-873-5p (miR-873-5p)/suppressor with the morphological effect on genitalia 1 (SMG1) axis on the progression of HCC. Bioinformatics databases were used to predict new HCC-related pathways. HCC cells were then selected for determining the expression of METTL3, miR-873-5p, and SMG1. Dual luciferase reporter gene assay, co-immunoprecipitation and RNA binding protein immunoprecipitation were employed to explore the relationship between miR-873-5p and SMG1, binding between METTL3 and DiGeorge critical region 8 (DGCR8), and the enrichment of DGCR8 and N6-methyladenosine (m6A) on pri-miR-873-5p, respectively. Additionally, the effect of METTL3 on the malignant phenotypes of HCC cells as well as the tumorigenicity of transfected cells were examined with gain-and-loss-of-function experiments. Bioinformatics databases suggested that METTL3 increased the expression of miR-873-5p in an m6A-dependent way, thereby suppressing the expression of SMG1 to promote the development of HCC. In HCC cells, miR-873-5p and METTL3 were highly expressed, while SMG1 was under-expressed. miR-873-5p promoted the malignant phenotypes in HCC cells by the negative regulation of SMG1. METTL3 promoted the m6A modification of pri-miR-873-5p, contributing to an increased expression of miR-873-5p. METTL3 also accelerated tumor formation in nude mice by down-regulating the expression of SMG1. Our study revealed that METTL3 inhibited the expression of SMG1 through m6A modification-mediated miR-873-5p up-regulation, thus playing an oncogenic role in HCC.
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