Sevelamer Improves Steatohepatitis, Inhibits Liver and Intestinal Farnesoid X Receptor (FXR), and Reverses Innate Immune Dysregulation in a Mouse Model of Non-alcoholic Fatty Liver Disease.
Bile acid sequestrants are synthetic polymers that bind bile acids in the gut and are used to treat dyslipidemia and hyperphosphatemia. Recently, these agents have been reported to lower blood glucose and increase insulin sensitivity by altering bile acid signaling pathways. In this study, we assessed the efficacy of sevelamer in treating mice with non-alcoholic fatty liver disease (NAFLD). We also analyzed how sevelamer alters inflammation and bile acid signaling in NAFLD livers. Mice were fed a low-fat or Western diet for 12 weeks followed by a diet-plus-sevelamer regimen for 2 or 12 weeks. At the end of treatment, disease severity was assessed, hepatic leukocyte populations were examined, and expression of genes involved in farnesoid X receptor (FXR) signaling in the liver and intestine was analyzed. Sevelamer treatment significantly reduced liver steatosis and lobular inflammation. Sevelamer-treated NAFLD livers had notably fewer pro-inflammatory infiltrating macrophages and a significantly greater fraction of alternatively activated Kupffer cells compared with controls. Expression of genes involved in FXR signaling in the liver and intestine was significantly altered in mice with NAFLD as well as in those treated with sevelamer. In a mouse model of NAFLD, sevelamer improved disease and counteracted innate immune cell dysregulation in the liver. This study also revealed a dysregulation of FXR signaling in the liver and intestine of NAFLD mice that was counteracted by sevelamer treatment.
From the Departments of Gastroenterology and Hepatology.|Immunology and Microbiology, University of Colorado, Aurora, Colorado 80045.
Brett M
0000-0002-3120-0123
BM
McGettigan
From the Departments of Gastroenterology and Hepatology.
Rachel H
RH
McMahan
Renal Diseases and Hypertension.
Yuhuan
Y
Luo
Renal Diseases and Hypertension.
Xiaoxin X
XX
Wang
Pathology, and.
David J
DJ
Orlicky
From the Departments of Gastroenterology and Hepatology.
Cara
C
Porsche
Renal Diseases and Hypertension.
Moshe
M
Levi
From the Departments of Gastroenterology and Hepatology, hugo.rosen@ucdenver.edu.|Immunology and Microbiology, University of Colorado, Aurora, Colorado 80045.
Hugo R
HR
Rosen
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D004195:Disease Models, Animal; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D000069603:Sevelamer / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects; D000099150:Receptor, Farnesoid X-Activated
D000893:Anti-Inflammatory Agents; D018160:Receptors, Cytoplasmic and Nuclear; D000069603:Sevelamer; D000099150:Receptor, Farnesoid X-Activated
FXR; NAFLD; bile acid; bile acid sequestrants; inflammation; innate immunity; macrophage; obesity; sevelamer; steatohepatitis