Pub Date : 2024-04-16DOI: 10.1152/ajpgi.00075.2024
Derek M. McKay, Manon Defaye, Sruthi Rajeev, Wallace K. MacNaughton, Yasmin Nasser, Keith A. Sharkey
American Journal of Physiology-Gastrointestinal and Liver Physiology, Ahead of Print.
美国生理学杂志-胃肠道和肝脏生理学》（American Journal of Physiology-Gastrointestinal and Liver Physiology），提前出版。
{"title":"Neuroimmunophysiology of the Gastrointestinal Tract","authors":"Derek M. McKay, Manon Defaye, Sruthi Rajeev, Wallace K. MacNaughton, Yasmin Nasser, Keith A. Sharkey","doi":"10.1152/ajpgi.00075.2024","DOIUrl":"https://doi.org/10.1152/ajpgi.00075.2024","url":null,"abstract":"American Journal of Physiology-Gastrointestinal and Liver Physiology, Ahead of Print. <br/>","PeriodicalId":7598,"journal":{"name":"American Journal of Physiology - Gastrointestinal and Liver Physiology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140615059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-16DOI: 10.1152/ajpgi.00047.2024
Anne-Sofie H. Jensen, Henriette Ytting, Mikkel P. Werge, Elias B. Rashu, Liv E. Hetland, Mira Thing, Puria Nabilou, Johan Burisch, Kirstine N. Bojsen-Møller, Anders E. Junker, Lise Hobolth, Christian Mortensen, Flemming Tofteng, Flemming Bendtsen, Søren Møller, Mogens Vyberg, Reza R. Serizawa, Lise L. Gluud, Nicolai J. Wewer Albrechtsen
Autoimmune liver diseases are associated with an increased risk of diabetes, yet the underlying mechanisms remain unknown. In this cross-sectional study, we investigated the glucose-regulatory disturbances in patients with autoimmune hepatitis (AIH, n=19), primary biliary cholangitis (PBC, n=15), and primary sclerosing cholangitis (PSC, n=6). Healthy individuals (n=24) and patients with metabolic dysfunction-associated steatotic liver disease (MASLD, n=18) were included as controls. Blood samples were collected during a 120 min oral glucose tolerance test. We measured the concentrations of glucose, C-peptide, insulin, glucagon, the two incretin hormones glucose insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). We calculated the homeostasis model assessment of insulin resistance (HOMA-IR), whole body insulin resistance (Matsuda index), insulin clearance, and insulinogenic index. All patient groups had increased fasting plasma glucose and impaired glucose responses compared with healthy controls. Beta-cell secretion was increased in AIH, PBC, and MASLD but not in PSC. AIH and MASLD patients had hyperglucagonemia and hepatic, as well as peripheral, insulin resistance and decreased insulin clearance, resulting in hyperinsulinemia. Patients with autoimmune liver disease had an increased GIP response, and those with AIH or PBC had an increased GLP-1 response. Our data demonstrate that the mechanism underlying glucose disturbances in patients with autoimmune liver disease differs from that underlying MASLD, including compensatory incretin responses in patients with autoimmune liver disease. Our results suggest that glucose disturbances are present at an early stage of the disease.
{"title":"Patients with autoimmune liver disease have glucose disturbances that mechanistically differ from steatotic liver disease","authors":"Anne-Sofie H. Jensen, Henriette Ytting, Mikkel P. Werge, Elias B. Rashu, Liv E. Hetland, Mira Thing, Puria Nabilou, Johan Burisch, Kirstine N. Bojsen-Møller, Anders E. Junker, Lise Hobolth, Christian Mortensen, Flemming Tofteng, Flemming Bendtsen, Søren Møller, Mogens Vyberg, Reza R. Serizawa, Lise L. Gluud, Nicolai J. Wewer Albrechtsen","doi":"10.1152/ajpgi.00047.2024","DOIUrl":"https://doi.org/10.1152/ajpgi.00047.2024","url":null,"abstract":"Autoimmune liver diseases are associated with an increased risk of diabetes, yet the underlying mechanisms remain unknown. In this cross-sectional study, we investigated the glucose-regulatory disturbances in patients with autoimmune hepatitis (AIH, n=19), primary biliary cholangitis (PBC, n=15), and primary sclerosing cholangitis (PSC, n=6). Healthy individuals (n=24) and patients with metabolic dysfunction-associated steatotic liver disease (MASLD, n=18) were included as controls. Blood samples were collected during a 120 min oral glucose tolerance test. We measured the concentrations of glucose, C-peptide, insulin, glucagon, the two incretin hormones glucose insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). We calculated the homeostasis model assessment of insulin resistance (HOMA-IR), whole body insulin resistance (Matsuda index), insulin clearance, and insulinogenic index. All patient groups had increased fasting plasma glucose and impaired glucose responses compared with healthy controls. Beta-cell secretion was increased in AIH, PBC, and MASLD but not in PSC. AIH and MASLD patients had hyperglucagonemia and hepatic, as well as peripheral, insulin resistance and decreased insulin clearance, resulting in hyperinsulinemia. Patients with autoimmune liver disease had an increased GIP response, and those with AIH or PBC had an increased GLP-1 response. Our data demonstrate that the mechanism underlying glucose disturbances in patients with autoimmune liver disease differs from that underlying MASLD, including compensatory incretin responses in patients with autoimmune liver disease. Our results suggest that glucose disturbances are present at an early stage of the disease.","PeriodicalId":7598,"journal":{"name":"American Journal of Physiology - Gastrointestinal and Liver Physiology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140614914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-16DOI: 10.1152/ajpgi.00049.2024
Ivan M. Lang, Bidyut K. Medda, Reza Shaker
During pharyngeal phase of swallowing circumferential tension of the cervical esophagus (CTE) increases caused by a biomechanical process of laryngeal elevation pulling the cervical esophagus orad. The esophagus contracts longitudinally during esophageal peristalsis, therefore, we hypothesized that CTE increases during esophageal peristalsis by a biomechanical process. Methods: We investigated this hypothesis using 28 decerebrate cats instrumented with EMG electrodes on the pharynx and esophagus, and esophageal manometry. We recorded CTE, distal esophageal longitudinal tension (DET), and orad laryngeal tension (OLT) using strain gauges. Peristalsis was stimulated by injecting saline into esophagus or nasopharynx. We investigated the effects of transecting the pharyngo-esophageal nerve (PEN), hypoglossal nerve (HG), or administering (10 mg/kg, IV) hexamethonium (HEX). Results: We found that the durations of CTE and DET increased and OLT decreased simultaneously during the total extent of esophageal peristalsis. CTE duration was highly correlated with DET, but not esophageal EMG or manometry. The peak magnitudes of the DET and CTE were highly correlated. After HEX administration, peristalsis in the distal esophagus did not occur, and the duration of the CTE response decreased. PEN transection blocked the occurrence of cricopharyngeal or cervical esophageal response during peristalsis, but had no significant effect on the CTE response. HG transection had no significant effect on CTE. Conclusion: We conclude that there is a significant CTE increase, independent of laryngeal elevation or esophageal muscle contraction, which occurs during esophageal peristalsis. This response is a biomechanical process caused by esophageal shortening that occurs during esophageal longitudinal contraction of esophageal peristalsis.
{"title":"Biomechanical Increase in Cervical Esophageal Wall Tension during Peristalsis","authors":"Ivan M. Lang, Bidyut K. Medda, Reza Shaker","doi":"10.1152/ajpgi.00049.2024","DOIUrl":"https://doi.org/10.1152/ajpgi.00049.2024","url":null,"abstract":"During pharyngeal phase of swallowing circumferential tension of the cervical esophagus (CTE) increases caused by a biomechanical process of laryngeal elevation pulling the cervical esophagus orad. The esophagus contracts longitudinally during esophageal peristalsis, therefore, we hypothesized that CTE increases during esophageal peristalsis by a biomechanical process. Methods: We investigated this hypothesis using 28 decerebrate cats instrumented with EMG electrodes on the pharynx and esophagus, and esophageal manometry. We recorded CTE, distal esophageal longitudinal tension (DET), and orad laryngeal tension (OLT) using strain gauges. Peristalsis was stimulated by injecting saline into esophagus or nasopharynx. We investigated the effects of transecting the pharyngo-esophageal nerve (PEN), hypoglossal nerve (HG), or administering (10 mg/kg, IV) hexamethonium (HEX). Results: We found that the durations of CTE and DET increased and OLT decreased simultaneously during the total extent of esophageal peristalsis. CTE duration was highly correlated with DET, but not esophageal EMG or manometry. The peak magnitudes of the DET and CTE were highly correlated. After HEX administration, peristalsis in the distal esophagus did not occur, and the duration of the CTE response decreased. PEN transection blocked the occurrence of cricopharyngeal or cervical esophageal response during peristalsis, but had no significant effect on the CTE response. HG transection had no significant effect on CTE. Conclusion: We conclude that there is a significant CTE increase, independent of laryngeal elevation or esophageal muscle contraction, which occurs during esophageal peristalsis. This response is a biomechanical process caused by esophageal shortening that occurs during esophageal longitudinal contraction of esophageal peristalsis.","PeriodicalId":7598,"journal":{"name":"American Journal of Physiology - Gastrointestinal and Liver Physiology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140615050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-09DOI: 10.1152/ajpgi.00254.2023
Nipuni D. Nagahawatte, Recep Avci, Niranchan Paskaranandavadivel, Leo K. Cheng
The motility of the gastrointestinal tract is coordinated in part by rhythmic slow waves, and disrupted slow wave patterns are linked to functional motility disorders. At present, there are no treatment strategies that primarily target slow wave activity. This study assessed the use of pacing to suppress glucagon-induced slow wave dysrhythmias in the small intestine. Slow waves in the jejunum were mapped in vivo using a high-resolution surface-contact electrode array in pigs (n=7). Glucagon was intravenously administered to induce hyperglycemia. Slow wave propagation patterns were categorized into antegrade, retrograde, collision, pacemaker and uncoupled activity. Slow wave characteristics such as period, amplitude and speed were also quantified. Post-glucagon infusion, pacing was applied at 4 mA and 8 mA and the resulting slow waves were quantified spatiotemporally. Antegrade propagation was dominant throughout all stages with a prevalence of 55 ± 38% at baseline. However, glucagon infusion resulted in a substantial and significant increase in uncoupled slow waves from 10 ± 8% to 30 ± 12% (p=0.004) without significantly altering the prevalence of other slow wave patterns. Slow wave frequency, amplitude and speed remained unchanged. Pacing, particularly at 8 mA, significantly suppressed dysrhythmic slow wave patterns and achieved more effective spatial entrainment (85%) compared to 4 mA (46%, p=0.039).This study defined the effect of glucagon on jejunal slow waves and identified uncoupling as a key dysrhythmia signature. Pacing effectively entrained rhythmic activity and suppressed dysrhythmias, highlighting the potential of pacing for gastrointestinal disorders associated with slow wave abnormalities.
{"title":"High-Energy Pacing Inhibits Slow Wave Dysrhythmias in the Small Intestine","authors":"Nipuni D. Nagahawatte, Recep Avci, Niranchan Paskaranandavadivel, Leo K. Cheng","doi":"10.1152/ajpgi.00254.2023","DOIUrl":"https://doi.org/10.1152/ajpgi.00254.2023","url":null,"abstract":"The motility of the gastrointestinal tract is coordinated in part by rhythmic slow waves, and disrupted slow wave patterns are linked to functional motility disorders. At present, there are no treatment strategies that primarily target slow wave activity. This study assessed the use of pacing to suppress glucagon-induced slow wave dysrhythmias in the small intestine. Slow waves in the jejunum were mapped <i>in vivo</i> using a high-resolution surface-contact electrode array in pigs (n=7). Glucagon was intravenously administered to induce hyperglycemia. Slow wave propagation patterns were categorized into antegrade, retrograde, collision, pacemaker and uncoupled activity. Slow wave characteristics such as period, amplitude and speed were also quantified. Post-glucagon infusion, pacing was applied at 4 mA and 8 mA and the resulting slow waves were quantified spatiotemporally. Antegrade propagation was dominant throughout all stages with a prevalence of 55 ± 38% at baseline. However, glucagon infusion resulted in a substantial and significant increase in uncoupled slow waves from 10 ± 8% to 30 ± 12% (p=0.004) without significantly altering the prevalence of other slow wave patterns. Slow wave frequency, amplitude and speed remained unchanged. Pacing, particularly at 8 mA, significantly suppressed dysrhythmic slow wave patterns and achieved more effective spatial entrainment (85%) compared to 4 mA (46%, p=0.039).This study defined the effect of glucagon on jejunal slow waves and identified uncoupling as a key dysrhythmia signature. Pacing effectively entrained rhythmic activity and suppressed dysrhythmias, highlighting the potential of pacing for gastrointestinal disorders associated with slow wave abnormalities.","PeriodicalId":7598,"journal":{"name":"American Journal of Physiology - Gastrointestinal and Liver Physiology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140598480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-09DOI: 10.1152/ajpgi.00024.2024
Genta Kakiyama, Kei Minowa, Nanah Bai-Kamara, Taishi Hashiguchi, William M. Pandak, Daniel Rodriguez-Agudo
Background and aims: Insufficient expression of steroidogenic acute regulatory lipid transfer protein 5 (StarD5) on liver cholesterol/lipid homeostasis is not clearly defined. Methods: The ablation of StarD5 was analyzed in mice on a normal or western diet (WD) to determine its importance in hepatic lipid accumulation and fibrosis compared to wild type (WT) mice. Rescue experiments in StarD5-/- mice and hepatocytes were performed. Results: In addition to increased hepatic triglyceride/cholesterol levels, global StarD5-/- mice fed a normal diet displayed reduced plasma triglycerides and liver VLDL secretion as compared with WT counterparts. Insulin levels and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) scoring were elevated, demonstrating developing insulin resistance (IR). WD fed StarD5-/- mice up-regulated TAZ expression with accelerated liver fibrosis when compared to WD-fed WT mice. CYP7B1's suppression coupled with chronic accumulation of toxic oxysterol levels correlated with presentation of fibrosis. 'Hepatocyte selective' StarD5 overexpression in StarD5-/- mice restored expression, reduced hepatic triglycerides, and improved HOMA-IR. Observations in 2 additional mouse and one human NASH model were supportive. Conclusions: StarD5's downregulation with hepatic lipid excess is a previously unappreciated physiologic function appearing to promote lipid storage for future needs. Conversely, StarD5's lingering downregulation with prolonged lipid/cholesterol excess accelerates fatty liver's transition to fibrosis; mediated via dysregulation in the oxysterol signaling pathway.
{"title":"StarD5 levels of expression correlate with onset and progression of steatosis and liver fibrosis","authors":"Genta Kakiyama, Kei Minowa, Nanah Bai-Kamara, Taishi Hashiguchi, William M. Pandak, Daniel Rodriguez-Agudo","doi":"10.1152/ajpgi.00024.2024","DOIUrl":"https://doi.org/10.1152/ajpgi.00024.2024","url":null,"abstract":"Background and aims: Insufficient expression of steroidogenic acute regulatory lipid transfer protein 5 (StarD5) on liver cholesterol/lipid homeostasis is not clearly defined. Methods: The ablation of StarD5 was analyzed in mice on a normal or western diet (WD) to determine its importance in hepatic lipid accumulation and fibrosis compared to wild type (WT) mice. Rescue experiments in StarD5<sup>-/-</sup> mice and hepatocytes were performed. Results: In addition to increased hepatic triglyceride/cholesterol levels, global StarD5<sup>-/-</sup> mice fed a normal diet displayed reduced plasma triglycerides and liver VLDL secretion as compared with WT counterparts. Insulin levels and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) scoring were elevated, demonstrating developing insulin resistance (IR). WD fed StarD5<sup>-/-</sup> mice up-regulated TAZ expression with accelerated liver fibrosis when compared to WD-fed WT mice. CYP7B1's suppression coupled with chronic accumulation of toxic oxysterol levels correlated with presentation of fibrosis. 'Hepatocyte selective' StarD5 overexpression in StarD5<sup>-/- </sup>mice restored expression, reduced hepatic triglycerides, and improved HOMA-IR. Observations in 2 additional mouse and one human NASH model were supportive. Conclusions: StarD5's downregulation with hepatic lipid excess is a previously unappreciated physiologic function appearing to promote lipid storage for future needs. Conversely, StarD5's lingering downregulation with prolonged lipid/cholesterol excess accelerates fatty liver's transition to fibrosis; mediated via dysregulation in the oxysterol signaling pathway.","PeriodicalId":7598,"journal":{"name":"American Journal of Physiology - Gastrointestinal and Liver Physiology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140598373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-09DOI: 10.1152/ajpgi.00269.2023
Beth B. McConnell, Zhongxing Liang, Chad Xu, Yiran Han, C. Chris Yun
Lysophosphatidic acid (LPA) is a bioactive lipid molecule that regulates a wide array of cellular functions, including proliferation, differentiation, and survival, via activation of cognate receptors. The LPA5 receptor is highly expressed in the intestinal epithelium, but its function in restoring intestinal epithelial integrity following injury has not been examined. Here, we use a radiation-induced injury model to study the role of LPA5 in regulating intestinal epithelial regeneration. Control mice (Lpar5f/f) and mice with an inducible, epithelial cell-specific deletion of Lpar5 in the small intestine (Lpar5IECKO) were subjected to 10 Gy total body X-ray irradiation and analyzed during recovery. Repair of the intestinal mucosa was delayed in Lpar5IECKO mice, with reduced epithelial proliferation and increased crypt cell apoptosis. These effects were accompanied by reduced numbers of OLFM4+ intestinal stem cells (ISCs). The effects of LPA5 on ISCs were corroborated by studies using organoids derived from Lgr5-lineage tracking reporter mice with deletion of Lpar5 in Lgr5+-stem cells (Lgr5Contor Lgr5ΔLpar5). Irradiation of organoids resulted in fewer numbers of Lgr5ΔLpar5 organoids retaining Lgr5+-derived progenitor cells compared to Lgr5Cont organoids. Finally, we observed that impaired regeneration in Lpar5IECKO mice was associated with reduced numbers of Paneth cells and decreased expression of YAP, a critical factor for intestinal epithelial repair. Our study highlights a novel role for LPA5 in regeneration of the intestinal epithelium following irradiation and its effect on the maintenance of Paneth cells that support the stem cell niche.
{"title":"LPA5-Dependent Signaling Regulates Regeneration of the Intestinal Epithelium Following Irradiation","authors":"Beth B. McConnell, Zhongxing Liang, Chad Xu, Yiran Han, C. Chris Yun","doi":"10.1152/ajpgi.00269.2023","DOIUrl":"https://doi.org/10.1152/ajpgi.00269.2023","url":null,"abstract":"Lysophosphatidic acid (LPA) is a bioactive lipid molecule that regulates a wide array of cellular functions, including proliferation, differentiation, and survival, via activation of cognate receptors. The LPA<sub>5</sub> receptor is highly expressed in the intestinal epithelium, but its function in restoring intestinal epithelial integrity following injury has not been examined. Here, we use a radiation-induced injury model to study the role of LPA<sub>5 </sub>in regulating intestinal epithelial regeneration. Control mice (<i>Lpar5<sup>f/f</sup></i>) and mice with an inducible, epithelial cell-specific deletion of <i>Lpar5</i> in the small intestine (<i>Lpar5<sup>IECKO</sup></i>) were subjected to 10 Gy total body X-ray irradiation and analyzed during recovery. Repair of the intestinal mucosa was delayed in <i>Lpar5<sup>IECKO</sup></i> mice, with reduced epithelial proliferation and increased crypt cell apoptosis. These effects were accompanied by reduced numbers of OLFM4<sup>+</sup> intestinal stem cells (ISCs). The effects of LPA<sub>5</sub> on ISCs were corroborated by studies using organoids derived from Lgr5-lineage tracking reporter mice with deletion of <i>Lpar5</i> in Lgr5+-stem cells <i>(Lgr5<sup>Cont</sup></i>or<i> Lgr5<sup>ΔLpar5</sup></i>). Irradiation of organoids resulted in fewer numbers of <i>Lgr5<sup>ΔLpar5 </sup></i>organoids retaining Lgr5+-derived progenitor cells compared to <i>Lgr5<sup>Cont</sup></i> organoids. Finally, we observed that impaired regeneration in <i>Lpar5<sup>IECKO</sup></i> mice was associated with reduced numbers of Paneth cells and decreased expression of YAP, a critical factor for intestinal epithelial repair. Our study highlights a novel role for LPA<sub>5</sub> in regeneration of the intestinal epithelium following irradiation and its effect on the maintenance of Paneth cells that support the stem cell niche.","PeriodicalId":7598,"journal":{"name":"American Journal of Physiology - Gastrointestinal and Liver Physiology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140598466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-09DOI: 10.1152/ajpgi.00273.2023
Xuemei Li, Xiaoqin Tang, Yue Xiang, Zhibo Zhao, Yanping Li, Qiuying Ding, Linkun Zhang, Jingyuan Xu, Lei Zhao, Yao Chen
Sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) is a widely expressed membrane glycoprotein that acts as an important modulator of lipid metabolism and inflammatory stress. N-glycosylation of SCAP has been suggested to modulate cancer development, but its role in NASH is poorly understood. In this study, the N-glycosylation of SCAP was analyzed by using sequential trypsin proteolysis and glycosidase treatment. The liver cell lines expressing wild-type and N-glycosylation sites mutated SCAP were constructed to investigate the N-glycosylation role of SCAP in regulating inflammation and lipid accumulation as well as the underlying mechanisms. The hepatic SCAP protein levels were significantly increased in C57BL/6J mice fed with western diet and sweet water (WD+SW) and diabetic db/db mice, which exhibited typical liver steatosis and inflammation. In vitro, the enhanced N-glycosylation increased the protein stability of SCAP and hence increased its total protein levels, while the ablation of N-glycosylation significantly decreased SCAP protein stability and alleviated lipid accumulation and inflammation in hepatic cell lines. Mechanistically, the presence of SCAP N-glycosylation increased not only the SREBP1-mediated acetyl-CoA synthetase 2 (ACSS2) transcription but also the AMPK-mediated S659 phosphorylation of ACCS2 protein, causing the enhanced ACSS2 levels in nucleus and hence increasing the histone H3K27 acetylation (H3K27ac), which is a key epigenetic modification associated with NASH. Modulating ACSS2 expression or its location in cytoplasm abolished the effects of SCAP N-glycosylation on H3K27ac and lipid accumulation and inflammation. In conclusion, SCAP N-glycosylation aggravates inflammation and lipid accumulation through enhancing ACSS2-mediated H3K27ac in hepatocytes.
{"title":"N-glycosylation of SCAP exacerbates hepatocellular inflammation and lipid accumulation via ACSS2-mediated histone H3K27 acetylation","authors":"Xuemei Li, Xiaoqin Tang, Yue Xiang, Zhibo Zhao, Yanping Li, Qiuying Ding, Linkun Zhang, Jingyuan Xu, Lei Zhao, Yao Chen","doi":"10.1152/ajpgi.00273.2023","DOIUrl":"https://doi.org/10.1152/ajpgi.00273.2023","url":null,"abstract":"Sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) is a widely expressed membrane glycoprotein that acts as an important modulator of lipid metabolism and inflammatory stress. N-glycosylation of SCAP has been suggested to modulate cancer development, but its role in NASH is poorly understood. In this study, the N-glycosylation of SCAP was analyzed by using sequential trypsin proteolysis and glycosidase treatment. The liver cell lines expressing wild-type and N-glycosylation sites mutated SCAP were constructed to investigate the N-glycosylation role of SCAP in regulating inflammation and lipid accumulation as well as the underlying mechanisms. The hepatic SCAP protein levels were significantly increased in C57BL/6J mice fed with western diet and sweet water (WD+SW) and diabetic db/db mice, which exhibited typical liver steatosis and inflammation. In vitro, the enhanced N-glycosylation increased the protein stability of SCAP and hence increased its total protein levels, while the ablation of N-glycosylation significantly decreased SCAP protein stability and alleviated lipid accumulation and inflammation in hepatic cell lines. Mechanistically, the presence of SCAP N-glycosylation increased not only the SREBP1-mediated acetyl-CoA synthetase 2 (ACSS2) transcription but also the AMPK-mediated S659 phosphorylation of ACCS2 protein, causing the enhanced ACSS2 levels in nucleus and hence increasing the histone H3K27 acetylation (H3K27ac), which is a key epigenetic modification associated with NASH. Modulating ACSS2 expression or its location in cytoplasm abolished the effects of SCAP N-glycosylation on H3K27ac and lipid accumulation and inflammation. In conclusion, SCAP N-glycosylation aggravates inflammation and lipid accumulation through enhancing ACSS2-mediated H3K27ac in hepatocytes.","PeriodicalId":7598,"journal":{"name":"American Journal of Physiology - Gastrointestinal and Liver Physiology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140598484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-09DOI: 10.1152/ajpgi.00259.2023
Glory Bui, Cristina Torres-Fuentes, Matteo M. Pusceddu, Melanie G. Gareau, Maria L. Marco
American Journal of Physiology-Gastrointestinal and Liver Physiology, Ahead of Print.
美国生理学杂志-胃肠道和肝脏生理学》（American Journal of Physiology-Gastrointestinal and Liver Physiology），提前出版。
{"title":"Milk and Lacticaseibacillus casei BL23 effects on intestinal responses in a murine model of colitis","authors":"Glory Bui, Cristina Torres-Fuentes, Matteo M. Pusceddu, Melanie G. Gareau, Maria L. Marco","doi":"10.1152/ajpgi.00259.2023","DOIUrl":"https://doi.org/10.1152/ajpgi.00259.2023","url":null,"abstract":"American Journal of Physiology-Gastrointestinal and Liver Physiology, Ahead of Print. <br/>","PeriodicalId":7598,"journal":{"name":"American Journal of Physiology - Gastrointestinal and Liver Physiology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140598454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-09DOI: 10.1152/ajpgi.00306.2023
Gaston H. Rueda, Natalia Causada-Calo, Rajka Borojevic, Andrea Nardelli, Maria Ines Pinto-Sanchez, Marco Constante, Josie Libertucci, Vidhyalakshmi Mohan, Philippe Langella, Linda M. P. Loonen, Jerry M. Wells, Harry Sokol, Elena F. Verdu, Premysl Bercik
American Journal of Physiology-Gastrointestinal and Liver Physiology, Ahead of Print.
美国生理学杂志-胃肠道和肝脏生理学》（American Journal of Physiology-Gastrointestinal and Liver Physiology），提前出版。
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