Cholesterol synthesis is increased and absorption decreased in non-alcoholic fatty liver disease independent of obesity

Simonen, Piia; Kotronen, Anna; Hallikainen, Maarit; Sevastianova, Ksenia; Makkonen, Janne; Hakkarainen, Antti; Lundbom, Nina; Miettinen, Tatu A.; Gylling, Helena; Yki-Järvinen, Hannele

doi:10.1016/j.jhep.2010.05.037

« Previous Next »Journal of Hepatology
Volume 54, Issue 1 , Pages 153-159, January 2011

Cholesterol synthesis is increased and absorption decreased in non-alcoholic fatty liver disease independent of obesity

Piia Simonen
- Department of Medicine, Division of Internal Medicine, University of Helsinki, Helsinki, Finland
- Corresponding author. Address: Biomedicum Helsinki, Room C422, P.O. Box 700 FIN-00029 HUS, Finland.
Anna Kotronen
- Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki, Finland
- Minerva Medical Research Institute, Helsinki, Finland
Maarit Hallikainen
- Department of Clinical Nutrition, University of Kuopio, Kuopio, Finland
- Department of Medicine, Kuopio University Hospital, Kuopio, Finland
Ksenia Sevastianova
- Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki, Finland
- Minerva Medical Research Institute, Helsinki, Finland
Janne Makkonen
- Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki, Finland
- Minerva Medical Research Institute, Helsinki, Finland
Antti Hakkarainen
- Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki, Finland
- Helsinki Medical Imaging Center, University of Helsinki, Helsinki, Finland
Nina Lundbom
- Helsinki Medical Imaging Center, University of Helsinki, Helsinki, Finland
Tatu A. Miettinen
- Department of Medicine, Division of Internal Medicine, University of Helsinki, Helsinki, Finland
Helena Gylling
- Department of Clinical Nutrition, University of Kuopio, Kuopio, Finland
- Department of Medicine, Kuopio University Hospital, Kuopio, Finland
Hannele Yki-Järvinen
- Department of Medicine, Division of Diabetes, University of Helsinki, Helsinki, Finland

Received 19 March 2010; received in revised form 7 May 2010; accepted 25 May 2010. published online 31 August 2010.

Background & Aims

Non-alcoholic fatty liver disease (NAFLD) is associated with impaired glucose and lipoprotein metabolism. However, the metabolism of cholesterol in NAFLD remains unexplored. We investigated how fatty liver influences cholesterol metabolism in 242 non-diabetic subjects.

Methods

Liver fat content was measured with proton magnetic resonance spectroscopy. Cholesterol metabolism was assayed with serum non-cholesterol sterols, surrogate markers of cholesterol synthesis and absorption. The analyses were performed with gas–liquid chromatography.

Results

A total of 114 subjects had NAFLD and 128 subjects had normal liver fat content. Non-cholesterol sterols reflecting cholesterol synthesis (cholestenol, desmosterol, and lathosterol) were higher, and those reflecting cholesterol absorption (cholestanol and plant sterols) were lower in subjects with NAFLD than in controls, independent of body mass index. Liver fat content was positively associated with markers of cholesterol synthesis (r=from 0.262 to 0.344, p<0.001 for all) and inversely associated with markers of cholesterol absorption (r=from −0.299 to −0.336, p<0.001 for all). In the entire study group, synthesis and absorption markers were interrelated, indicating that the homeostasis of cholesterol metabolism was maintained. LDL cholesterol was similar in the two groups.

Conclusions

We demonstrated that although LDL cholesterol concentrations are unchanged, cholesterol metabolism in NAFLD is characterized by increased synthesis and diminished absorption of cholesterol. These changes are associated with liver fat content independent of body weight.

Keywords: Non-alcoholic fatty liver disease, Cholesterol absorption, Cholesterol synthesis, Lathosterol, Sitosterol, Cholestanol, Magnetic resonance spectroscopy

Abbreviations: NAFLD, non-alcoholic fatty liver disease, VLDL, very low density lipoprotein, HDL, high density lipoprotein, ¹H-MRS, proton magnetic resonance spectroscopy, HbA_1c, haemoglobin A_1c, LDL, low density lipoprotein, ALT, alanine aminotransferase, AST, aspartate aminotransferase, TE, echo time, TR, repetition time, TM, mixing time, BMI, body mass index, SREBP, sterol regulatory element-binding protein, SCAP, SREBP cleavage-activating protein, ACAT, acyl CoA-cholesterol acyltransferase, NPC1L1, Niemann-Pick C1-like-1