Z Gastroenterol 2020; 58(01): e5
DOI: 10.1055/s-0039-3402110
Lectures Session III Metabolism (incl. NAFLD): Friday, February 14, 2020, 6:20 pm – 7:05 pm, Lecture Hall P1
Georg Thieme Verlag KG Stuttgart · New York

Genes involved in hepatic cholesterol homeostasis identified as modifiers of cholestasis in Abcb4 deficient mice

R Hall
1   Saarland University Medical Center, Department of Medicine 2, Homburg, Germany
,
M Krawczyk
1   Saarland University Medical Center, Department of Medicine 2, Homburg, Germany
2   Medical University of Warsaw, Department of General Transplant and Liver Surgery, Warsaw, Poland
,
S Weber
1   Saarland University Medical Center, Department of Medicine 2, Homburg, Germany
,
M Milkiewicz
3   Pomeranian Medical University, Department of Medical Biology, Szeczecin, Poland
,
P Milkiewicz
4   Medical University of Warsaw, Liver and Internal Medicine Unit, Warsaw, Poland
,
F Lammert
1   Saarland University Medical Center, Department of Medicine 2, Homburg, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
03 January 2020 (online)

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Background:

The severity of ABCB4-related liver diseases varies with transporter functionality and genetic predisposition. Modifier genes have yet to be investigated. In the Abcb4-/- mouse model, deficiency of the hepatobiliary phosphatidylcholine translocase causes chronic cholangiopathy and biliary fibrosis. Recently we identified fibrogenic quantitative trait loci (QTL) in an experimental cross of congenic FVB- and BALB-Abcb4-/- knockout strains and potential candidate genes regulating hepatic cholesterol metabolism. Among these we investigated the role of Pcsk9 (proprotein convertase subtilin-kexin type 9), which controls the degradation of the LDL receptor, in Abcb4-/- and wild-type mice. In addition, we analysed the association of PCSK9 variants in patients with primary sclerosing cholangitis (PSC).

Patients and Methods:

Hepatic injury was characterized by measurement of collagen accumulation via colorimetric measurement of hydroxyproline and serum surrogate markers (ALT, AP). We determined plasma lipid profiles and hepatic steady-state mRNA expression of Pcsk9, Hmgcr, Ldlr and Srebp2 as important regulators of cholesterol homeostasis. Genetic variation in the orthologous PCSK9 locus was tested in a cohort of 193 patients with PSC using Taqman assays.

Results:

Pcsk9 expression is significantly (p = 0.01) higher in FVB mice as compared to fibrotic BALB-Abcb4-/- mice. Irrespective of genetic background, wild-type mice display significantly (p = 0.01) higher Pcsk9 mRNA levels than knockouts. Concomitantly, plasma cholesterol levels are significantly (p < 0.01) higher in controls than in Abcb4 deficient mice and highest in FVB mice. Hmgcr expression is significantly (p < 0.05) reduced in susceptible BALB-Abcb4-/- mice. The genetic analysis of the PSC cohort revealed that carriers of the variant rs562556 PCSK9 allele presented with significantly (p = 0.017) higher serum AP activity, the bona fide surrogate marker of PSC severity.

Conclusions:

The analysis of ABCB4-dependent modifiers of cholestatic liver disease indicate that increased cholesterol levels correspond to higher Pcsk9 mRNA levels in fibrotic livers. PCSK9 variants might be associated with disease severity in PSC patients. We speculate that higher PCSK9 levels in livers of Abcb4-/- mice might be hepatoprotective, since they reduce the deleterious consequences of intrahepatic cholesterol accumulation.