Cholesterol-lowering drugs cause dissolution of cholesterol crystals and disperse Kupffer cell crown-like structures during resolution of NASH
Cholesterol crystals form within hepatocyte lipid droplets in human and experimental nonalcoholic steatohepatitis (NASH) and are the focus of crown-like structures (CLSs) of activated Kupffer cells (KCs). Obese, diabetic Alms1 mutant (foz/foz) mice were a fed high-fat (23%) diet containing 0.2% chol...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2015-02-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520356133 |
| _version_ | 1819293786060095488 |
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| author | George N. Ioannou Derrick M. Van Rooyen Christopher Savard W. Geoffrey Haigh Matthew M. Yeh Narci C. Teoh Geoffrey C. Farrell |
| author_facet | George N. Ioannou Derrick M. Van Rooyen Christopher Savard W. Geoffrey Haigh Matthew M. Yeh Narci C. Teoh Geoffrey C. Farrell |
| author_sort | George N. Ioannou |
| collection | DOAJ |
| description | Cholesterol crystals form within hepatocyte lipid droplets in human and experimental nonalcoholic steatohepatitis (NASH) and are the focus of crown-like structures (CLSs) of activated Kupffer cells (KCs). Obese, diabetic Alms1 mutant (foz/foz) mice were a fed high-fat (23%) diet containing 0.2% cholesterol for 16 weeks and then assigned to four intervention groups for 8 weeks: a) vehicle control, b) ezetimibe (5 mg/kg/day), c) atorvastatin (20 mg/kg/day), or d) ezetimibe and atorvastatin. Livers of vehicle-treated mice developed fibrosing NASH with abundant cholesterol crystallization within lipid droplets calculated to extend over 3.3% (SD, 2.2%) of liver surface area. Hepatocyte lipid droplets with prominent cholesterol crystallization were surrounded by TNFα-positive (activated) KCs forming CLSs (≥3 per high-power field). KCs that formed CLSs stained positive for NLRP3, implicating activation of the NLRP3 inflammasome in response to cholesterol crystals. In contrast, foz/foz mice treated with ezetimibe and atorvastatin showed near-complete resolution of cholesterol crystals [0.01% (SD, 0.02%) of surface area] and CLSs (0 per high-power field), with amelioration of fibrotic NASH. Ezetimibe or atorvastatin alone had intermediate effects on cholesterol crystallization, CLSs, and NASH. These findings are consistent with a causative link between exposure of hepatocytes and KCs to cholesterol crystals and with the development of NASH possibly mediated by NLRP3 activation. |
| first_indexed | 2024-12-24T04:15:57Z |
| format | Article |
| id | doaj.art-228bae4d70a1443cb3f82ef6233eeb08 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-24T04:15:57Z |
| publishDate | 2015-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-228bae4d70a1443cb3f82ef6233eeb082022-12-21T17:15:57ZengElsevierJournal of Lipid Research0022-22752015-02-01562277285Cholesterol-lowering drugs cause dissolution of cholesterol crystals and disperse Kupffer cell crown-like structures during resolution of NASHGeorge N. Ioannou0Derrick M. Van Rooyen1Christopher Savard2W. Geoffrey Haigh3Matthew M. Yeh4Narci C. Teoh5Geoffrey C. Farrell6To whom correspondence should be addressed; Division of Gastroenterology, Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, WA; To whom correspondence should be addressedLiver Research Group, Australian National University Medical School at the Canberra Hospital, Garran, ACT, AustraliaDivision of Gastroenterology, Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, WADivision of Gastroenterology, Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, WADepartment of Pathology, University of Washington, Seattle, WALiver Research Group, Australian National University Medical School at the Canberra Hospital, Garran, ACT, AustraliaLiver Research Group, Australian National University Medical School at the Canberra Hospital, Garran, ACT, AustraliaCholesterol crystals form within hepatocyte lipid droplets in human and experimental nonalcoholic steatohepatitis (NASH) and are the focus of crown-like structures (CLSs) of activated Kupffer cells (KCs). Obese, diabetic Alms1 mutant (foz/foz) mice were a fed high-fat (23%) diet containing 0.2% cholesterol for 16 weeks and then assigned to four intervention groups for 8 weeks: a) vehicle control, b) ezetimibe (5 mg/kg/day), c) atorvastatin (20 mg/kg/day), or d) ezetimibe and atorvastatin. Livers of vehicle-treated mice developed fibrosing NASH with abundant cholesterol crystallization within lipid droplets calculated to extend over 3.3% (SD, 2.2%) of liver surface area. Hepatocyte lipid droplets with prominent cholesterol crystallization were surrounded by TNFα-positive (activated) KCs forming CLSs (≥3 per high-power field). KCs that formed CLSs stained positive for NLRP3, implicating activation of the NLRP3 inflammasome in response to cholesterol crystals. In contrast, foz/foz mice treated with ezetimibe and atorvastatin showed near-complete resolution of cholesterol crystals [0.01% (SD, 0.02%) of surface area] and CLSs (0 per high-power field), with amelioration of fibrotic NASH. Ezetimibe or atorvastatin alone had intermediate effects on cholesterol crystallization, CLSs, and NASH. These findings are consistent with a causative link between exposure of hepatocytes and KCs to cholesterol crystals and with the development of NASH possibly mediated by NLRP3 activation.http://www.sciencedirect.com/science/article/pii/S0022227520356133crown-like structurecaspase 1lipotoxicitynonalcoholic steatohepatitis |
| spellingShingle | George N. Ioannou Derrick M. Van Rooyen Christopher Savard W. Geoffrey Haigh Matthew M. Yeh Narci C. Teoh Geoffrey C. Farrell Cholesterol-lowering drugs cause dissolution of cholesterol crystals and disperse Kupffer cell crown-like structures during resolution of NASH Journal of Lipid Research crown-like structure caspase 1 lipotoxicity nonalcoholic steatohepatitis |
| title | Cholesterol-lowering drugs cause dissolution of cholesterol crystals and disperse Kupffer cell crown-like structures during resolution of NASH |
| title_full | Cholesterol-lowering drugs cause dissolution of cholesterol crystals and disperse Kupffer cell crown-like structures during resolution of NASH |
| title_fullStr | Cholesterol-lowering drugs cause dissolution of cholesterol crystals and disperse Kupffer cell crown-like structures during resolution of NASH |
| title_full_unstemmed | Cholesterol-lowering drugs cause dissolution of cholesterol crystals and disperse Kupffer cell crown-like structures during resolution of NASH |
| title_short | Cholesterol-lowering drugs cause dissolution of cholesterol crystals and disperse Kupffer cell crown-like structures during resolution of NASH |
| title_sort | cholesterol lowering drugs cause dissolution of cholesterol crystals and disperse kupffer cell crown like structures during resolution of nash |
| topic | crown-like structure caspase 1 lipotoxicity nonalcoholic steatohepatitis |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520356133 |
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