Cholesterol crystallization within hepatocyte lipid droplets and its role in murine NASH
Ioannou GN, Subramanian S, Chait A, Haigh WG, Yeh MM, Farrell GC, Lee SP, Savard C
Journal of lipid research · 152 citations
Review labels
Neutral facts our review recorded about how this study was done. They describe method, never whether we like the result.
How it was studied
- Design
- Animal study (classified by our AI screen)
- Studied in
- People, plus animal or lab work
- Main outcome
- Mechanisms only
Who paid for it
- Funding
- Independent funding
- Government
- U.S. Department of Veterans Affairs
- University or hospital
- University of Washington
- University or hospital
- Diabetes Research Center, University of Washington
- Government
- National Institute of Diabetes and Digestive and Kidney Diseases
- Government
- NIDDK NIH HHS
- Government
- BLRD VA
- Government
- Veterans Affairs Biomedical and Laboratory Research and Development
- Grants
- National Institute of Diabetes and Digestive and Kidney Diseases (P30‐DK‐017047); U.S. Department of Veterans Affairs (I01 BX002910)
Based on 7 listed funder(s).
Publication
- Published
- 2017-04-13 · J Lipid Res · vol. 58 · issue 6 · pp. 1067–1079
- Publisher
- Elsevier BV
- Cited
- 180 citations · more than 97% of similar papers · 5.5× the field average
- Impact
- Top 10% most cited in its field
- References
- 50 works
- Access
- Open access (hybrid journal) · CC-BY
- Research areas
- Lipid metabolism and biosynthesis · Liver Disease Diagnosis and Treatment · Sphingolipid Metabolism and Signaling
- Keywords
- Cholesterol, Lipid droplet, Chemistry, Hepatocyte, Reverse cholesterol transport, Internal medicine, Endocrinology, Steatosis, Biochemistry, Lipoprotein, Biology, Medicine, In vitro
- MeSH
- kupffer cells, hepatocytes, animals, mice, inbred c57bl, humans, mice, cholesterol, cholesterol, dietary, crystallization, enzyme activation, dose-response relationship, drug, male, hep g2 cells, diet, high-fat, non-alcoholic fatty liver disease, lipid droplets, thp-1 cells
8 authors
From US, AU
- George N. Ioannou · correspondingUniversity of Washington; VA Puget Sound Health Care System
- Savitha SubramanianUniversity of Washington
- Alan ChaitUniversity of Washington
- W. Geoffrey HaighVA Puget Sound Health Care System
- Matthew M. YehUniversity of Washington
- Geoffrey C. FarrellAustralian National University; Canberra Hospital
Abstract
We recently reported that cholesterol crystals form in hepatocyte lipid droplets (LDs) in human and experimental nonalcoholic steatohepatitis. Herein, we assigned WT C57BL/6J mice to a high-fat (15%) diet for 6 months, supplemented with 0%, 0.25%, 0.5%, 0.75%, or 1% dietary cholesterol. Increasing dietary cholesterol led to cholesterol loading of the liver, but not of adipose tissue, resulting in fibrosing steatohepatitis at a dietary cholesterol concentration of ≥0.5%, whereas mice on lower-cholesterol diets developed only simple steatosis. Hepatic cholesterol crystals and crown-like structures also developed at a dietary cholesterol concentration ≥0.5%. Crown-like structures consisted of activated Kupffer cells (KCs) staining positive for NLRP3 and activated caspase 1, which surrounded and processed cholesterol crystal-containing remnant LDs of dead hepatocytes. The KCs processed LDs at the center of crown-like structures in the extracellular space by lysosomal enzymes, ultimately transforming into lipid-laden foam cells. When HepG2 cells were exposed to LDL cholesterol, they developed cholesterol crystals in LD membranes, which caused activation of THP1 cells (macrophages) grown in coculture; upregulation of TNF-alpha, NLRP3, and interleukin 1beta (IL1β) mRNA; and secretion of IL-1beta. In conclusion, cholesterol crystals form on the LD membrane of hepatocytes and cause activation and cholesterol loading of KCs that surround and process these LDs by lysosomal enzymes.
Abstract via Europe PMC. Copyright remains with the authors or publisher (CC BY).
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