Inhibition of chylomicron assembly leads to dissociation of hepatic steatosis from inflammation and fibrosis
Regulating dietary fat absorption may impact progression of nonalcoholic fatty liver disease (NAFLD). Here, we asked if inducible inhibition of chylomicron assembly, as observed in intestine-specific microsomal triglyceride (TG) transfer protein knockout mice (Mttp-IKO), could retard NAFLD progressi...
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doaj-0c35045f52da405ab6550600e4fa1d2b2021-10-11T04:14:23ZengElsevierJournal of Lipid Research0022-22752021-01-0162100123Inhibition of chylomicron assembly leads to dissociation of hepatic steatosis from inflammation and fibrosisYan Xie0Elizabeth P. Newberry1Elizabeth M. Brunt2Samuel J. Ballentine3Saeed Soleymanjahi4Elizabeth A. Molitor5Nicholas O. Davidson6Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USADivision of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USADepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USADepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USADivision of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USADivision of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USADivision of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; For correspondence: Nicholas O. DavidsonRegulating dietary fat absorption may impact progression of nonalcoholic fatty liver disease (NAFLD). Here, we asked if inducible inhibition of chylomicron assembly, as observed in intestine-specific microsomal triglyceride (TG) transfer protein knockout mice (Mttp-IKO), could retard NAFLD progression and/or reverse established fibrosis in two dietary models. Mttp-IKO mice fed a methionine/choline-deficient (MCD) diet exhibited reduced hepatic TGs, inflammation, and fibrosis, associated with reduced oxidative stress and downstream activation of c-Jun N-terminal kinase and nuclear factor kappa B signaling pathways. However, when Mttpflox mice were fed an MCD for 5 weeks and then administered tamoxifen to induce Mttp-IKO, hepatic TG was reduced, but inflammation and fibrosis were increased after 10 days of reversal along with adaptive changes in hepatic lipogenic mRNAs. Extending the reversal time, following 5 weeks of MCD feeding to 30 days led to sustained reductions in hepatic TG, but neither inflammation nor fibrosis was decreased, and both intestinal permeability and hepatic lipogenesis were increased. In a second model, similar reductions in hepatic TG were observed when mice were fed a high-fat/high-fructose/high-cholesterol (HFFC) diet for 10 weeks, then switched to chow ± tamoxifen (HFFC → chow) or (HFFC → Mttp-IKO chow), but again neither inflammation nor fibrosis was affected. In conclusion, we found that blocking chylomicron assembly attenuates MCD-induced NAFLD progression by reducing steatosis, oxidative stress, and inflammation. In contrast, blocking chylomicron assembly in the setting of established hepatic steatosis and fibrosis caused increased intestinal permeability and compensatory shifts in hepatic lipogenesis that mitigate resolution of inflammation and fibrogenic signaling despite 50–90-fold reductions in hepatic TG.http://www.sciencedirect.com/science/article/pii/S002222752100105Xintestinelipid absorptionantioxidantapolipoprotein Blipoproteinsmicrosomal triglyceride transfer protein |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yan Xie Elizabeth P. Newberry Elizabeth M. Brunt Samuel J. Ballentine Saeed Soleymanjahi Elizabeth A. Molitor Nicholas O. Davidson |
spellingShingle |
Yan Xie Elizabeth P. Newberry Elizabeth M. Brunt Samuel J. Ballentine Saeed Soleymanjahi Elizabeth A. Molitor Nicholas O. Davidson Inhibition of chylomicron assembly leads to dissociation of hepatic steatosis from inflammation and fibrosis Journal of Lipid Research intestine lipid absorption antioxidant apolipoprotein B lipoproteins microsomal triglyceride transfer protein |
author_facet |
Yan Xie Elizabeth P. Newberry Elizabeth M. Brunt Samuel J. Ballentine Saeed Soleymanjahi Elizabeth A. Molitor Nicholas O. Davidson |
author_sort |
Yan Xie |
title |
Inhibition of chylomicron assembly leads to dissociation of hepatic steatosis from inflammation and fibrosis |
title_short |
Inhibition of chylomicron assembly leads to dissociation of hepatic steatosis from inflammation and fibrosis |
title_full |
Inhibition of chylomicron assembly leads to dissociation of hepatic steatosis from inflammation and fibrosis |
title_fullStr |
Inhibition of chylomicron assembly leads to dissociation of hepatic steatosis from inflammation and fibrosis |
title_full_unstemmed |
Inhibition of chylomicron assembly leads to dissociation of hepatic steatosis from inflammation and fibrosis |
title_sort |
inhibition of chylomicron assembly leads to dissociation of hepatic steatosis from inflammation and fibrosis |
publisher |
Elsevier |
series |
Journal of Lipid Research |
issn |
0022-2275 |
publishDate |
2021-01-01 |
description |
Regulating dietary fat absorption may impact progression of nonalcoholic fatty liver disease (NAFLD). Here, we asked if inducible inhibition of chylomicron assembly, as observed in intestine-specific microsomal triglyceride (TG) transfer protein knockout mice (Mttp-IKO), could retard NAFLD progression and/or reverse established fibrosis in two dietary models. Mttp-IKO mice fed a methionine/choline-deficient (MCD) diet exhibited reduced hepatic TGs, inflammation, and fibrosis, associated with reduced oxidative stress and downstream activation of c-Jun N-terminal kinase and nuclear factor kappa B signaling pathways. However, when Mttpflox mice were fed an MCD for 5 weeks and then administered tamoxifen to induce Mttp-IKO, hepatic TG was reduced, but inflammation and fibrosis were increased after 10 days of reversal along with adaptive changes in hepatic lipogenic mRNAs. Extending the reversal time, following 5 weeks of MCD feeding to 30 days led to sustained reductions in hepatic TG, but neither inflammation nor fibrosis was decreased, and both intestinal permeability and hepatic lipogenesis were increased. In a second model, similar reductions in hepatic TG were observed when mice were fed a high-fat/high-fructose/high-cholesterol (HFFC) diet for 10 weeks, then switched to chow ± tamoxifen (HFFC → chow) or (HFFC → Mttp-IKO chow), but again neither inflammation nor fibrosis was affected. In conclusion, we found that blocking chylomicron assembly attenuates MCD-induced NAFLD progression by reducing steatosis, oxidative stress, and inflammation. In contrast, blocking chylomicron assembly in the setting of established hepatic steatosis and fibrosis caused increased intestinal permeability and compensatory shifts in hepatic lipogenesis that mitigate resolution of inflammation and fibrogenic signaling despite 50–90-fold reductions in hepatic TG. |
topic |
intestine lipid absorption antioxidant apolipoprotein B lipoproteins microsomal triglyceride transfer protein |
url |
http://www.sciencedirect.com/science/article/pii/S002222752100105X |
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