Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Aug 8, 2016; 8(22): 924-932
Published online Aug 8, 2016. doi: 10.4254/wjh.v8.i22.924
Cholesterol metabolism in cholestatic liver disease and liver transplantation: From molecular mechanisms to clinical implications
Katriina Nemes, Fredrik Åberg, Helena Gylling, Helena Isoniemi
Katriina Nemes, Fredrik Åberg, Helena Isoniemi, University of Helsinki and Helsinki University Central Hospital, Transplantation and Liver Surgery Clinic, Meilahti Hospital, P.O. BOX 340, FI-00029 HUS, Finland
Helena Gylling, University of Helsinki and Helsinki University Central Hospital, Internal Medicine, Biomedicum Helsinki C 4 22, P.O. BOX 700, FI-00029 HUS, Finland
Author contributions: Nemes K wrote the first draft; Åberg F made critical revisions and constructed the figures; Gylling H and Isoniemi H further revised the manuscript; all authors have approved the final version of the manuscript and its submission.
Conflict-of-interest statement: The authors declare no conflict of interests for this article.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Katriina Nemes, MD, PhD, University of Helsinki and Helsinki University Central Hospital, Transplantation and Liver Surgery Clinic, Meilahti Hospital, P.O. BOX 340, FI-00029 HUS, Finland.
Telephone: +358-40-5002151 Fax: +358-9-174975
Received: March 31, 2016
Peer-review started: April 6, 2016
First decision: May 17, 2016
Revised: June 7, 2016
Accepted: July 11, 2016
Article in press: July 13, 2016
Published online: August 8, 2016

The aim of this review is to enlighten the critical roles that the liver plays in cholesterol metabolism. Liver transplantation can serve as gene therapy or a source of gene transmission in certain conditions that affect cholesterol metabolism, such as low-density-lipoprotein (LDL) receptor gene mutations that are associated with familial hypercholesterolemia. On the other hand, cholestatic liver disease often alters cholesterol metabolism. Cholestasis can lead to formation of lipoprotein X (Lp-X), which is frequently mistaken for LDL on routine clinical tests. In contrast to LDL, Lp-X is non-atherogenic, and failure to differentiate between the two can interfere with cardiovascular risk assessment, potentially leading to prescription of futile lipid-lowering therapy. Statins do not effectively lower Lp-X levels, and cholestasis may lead to accumulation of toxic levels of statins. Moreover, severe cholestasis results in poor micellar formation, which reduces cholesterol absorption, potentially impairing the cholesterol-lowering effect of ezetimibe. Apolipoprotein B-100 measurement can help distinguish between atherogenic and non-atherogenic hypercholesterolemia. Furthermore, routine serum cholesterol measurements alone cannot reflect cholesterol absorption and synthesis. Measurements of serum non-cholesterol sterol biomarkers - such as cholesterol precursor sterols, plant sterols, and cholestanol - may help with the comprehensive assessment of cholesterol metabolism. An adequate cholesterol supply is essential for liver-regenerative capacity. Low preoperative and perioperative serum cholesterol levels seem to predict mortality in liver cirrhosis and after liver transplantation. Thus, accurate lipid profile evaluation is highly important in liver disease and after liver transplantation.

Keywords: Cholesterol metabolism, Cholestasis, Liver transplantation, Non-cholesterol sterols, Cholestanol, Donor, Low density lipoprotein receptor mutation, Apolipoprotein B-100, Lipoprotein-X

Core tip: The liver plays key roles in cholesterol metabolism. Cholestatic liver disease leads to alterations of cholesterol metabolism: Cholesterol homeostasis is disturbed and cholesterol synthesis and especially cholesterol absorption are reduced, and lipoprotein X may develop. The latter can interfere with cardiovascular risk assessment. Apolipoprotein B-100 measurement may be useful in such cases. Cholesterol metabolism in cholestasis could be better described using cholesterol precursor sterols, diet-derived plant sterols, and cholestanol (the liver-synthesized derivate of cholesterol). Accurate lipid profile evaluation is particularly important after liver transplantation, when both atherogenic and non-atherogenic hypercholesterolemia may co-exist.