27-Hydroxycholesterol: a potential treatment for non-alcoholic
steatohepatitis in mice
SMA Walenbergh1, V Bieghs1, T Hendrikx1, PJ van Gorp1, F Verheyen1, YD
Guichot1, MLJ Jeurissen1, MJ Gijbels1, SS Rensen1, A Bast1, J Plat,1 SC Kalhan2, E
Leitersdorf3, GH Koek1, MH Hofker4, D Lütjohann5, R Shiri-Sverdlov1
1
Departments of Molecular Genetics, Molecular Cell Biology, Electron Microscopy,
Pathology, General Surgery, Toxicology, Internal Medicine and Human Biology;
Nutrition and Toxicology Research (NUTRIM) and Cardiovascular Research (CARIM)
Institutes of Maastricht, University of Maastricht, Maastricht University Medical Center
(MUMC), Maastricht, The Netherlands
2
Department of Pathobiology, Lerner Research Institute, The Cleveland Clinic
Foundation, Cleveland, Ohio
3
Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem,
Israel
4
Department of Pathology and Laboratory Medicine, University Medical Center
Groningen, University of Groningen, Groningen, The Netherlands
5
Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn,
Germany
Non-alcoholic steatohepatitis (NASH) is characterized by hepatic steatosis in
combination with inflammation. While steatosis itself is considered benign and reversible,
the presence of inflammation can lead to further liver damage. We recently demonstrated
a clear association between hepatic inflammation and lysosomal cholesterol accumulation
inside Kupffer cells (KCs). 27-hydroxycholesterol (27HC), a derivative of cholesterol
formed by CYP27A1, has been shown in vitro to mobilize cholesterol from the
lysosomes to the cytoplasm. Here, we hypothesized that 27HC can redirect the
intracellular cholesterol distribution in vivo, thereby influencing hepatic inflammation.
To investigate the role of CYP27A1 in NASH, irradiated low density lipoprotein receptor
knockout (Ldlr-/-) mice were transplanted (tp) with Cyp27a1-/- and wild-type (Wt) bone
marrow. After 9 weeks recovery, mice were fed either regular chow or a high-fat, high-
cholesterol (HFC) diet for 3 months. To examine whether exogenous 27HC influences
intracellular cholesterol distribution and hepatic inflammation, 27HC was administered to
Ldlr-/- mice that received regular chow or an HFC diet for 3 weeks.
Electron microscopy analysis of KCs revealed more lysosomal cholesterol accumulation
in Cyp27a1-/--tp mice than in Wt-tp mice after HFC feeding. Liver histology and gene
expression showed increased inflammation and liver damage in HFC-fed Cyp27a1-/--tp
mice. In line with these data, administration of 27HC to Ldlr-/- mice on an HFC diet led to
reduced lysosomal cholesterol accumulation and hepatic inflammation.
Conclusions:
These data support a causal role for lysosomal cholesterol accumulation in hepatic
inflammation and underline the potential of 27HC as a treatment for NASH.