Cholesterol metabolism in cholestatic liver disease and liver transplantation: From molecular mechanisms to clinical implications

Abstract

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.

Atypical Antipsychotic Drug Olanzapine Deregulates Hepatic Lipid Metabolism and Aortic Inflammation and Aggravates Atherosclerosis

“…It is well established that dietary fats and those from de novo lipogenesis in the liver are the two main sources for circulating total cholesterol and triglycerides, which are carried in circulation as VLDL. Elevated circulating total cholesterol and triglycerides may be attributed to increased lipid synthesis, or decreased lipid clearance, or both in the liver [13][14][15][16][17]. In this study, no difference was found in food intake between vehicle-treated mice and olanzapine-treated mice (data not shown).…”

“…5A-C). Olanzapine deregulates hepatic cholesterol and triglyceride metabolism in apoE -/-mice Hepatic cholesterol and triglyceride metabolism are crucial factors for maintaining the homeostasis of the lipid pool [13,14]. Thus, the effects of olanzapine on hepatic de novo lipogenesis, lipoprotein metabolism, triglyceride synthesis, and secretion, as well as fatty acid oxidation were investigated.…”

“…The liver is the major organ for both cholesterol production and cholesterol excretion from the human body [13,14]. The balance between the delivery of apoB-containing lipoproteins (chylomicron remnants, very low-density lipoprotein [VLDL], intermediatedensity lipoprotein and LDL) from the liver to peripheral tissues and high-density lipoprotein (HDL)-mediated reverse-cholesterol transport from tissues back to the liver is a crucial mechanism for maintaining the appropriate levels of circulating cholesterol [15].…”

Toxic epidermal necrolysis with severe hepatic involvement

“…In a series of 36 cases of TEN with DILI, none of the patients with similar bilirubin serum levels survived [8]. Moreover, hypercholesterolemia is usually associated with episodes of cholestasis [10], and this is also common in cholestatic DILI [9,11,12]. In our patient, cholesterol values took a long time to normalize ( Table 1).…”

The effects of coenzyme Q10 supplement on blood lipid indices and hepatic antioxidant defense system in SD rats fed a high cholesterol diet

“…CoQ 10 , a ubiquinone redox-active lipophilic antioxidant which is synthesized in the phospholipid membrane of the tissues, seems to play a crucial role in antioxidant system in various organs of animals. Among various organs, the liver is the major organ of cholesterol metabolism including biosynthesis, storage, excretion and converting cholesterol to bile acids under normal circumstances [30]. Therefore, it is necessary to explore the effects of CoQ 10 on the expression of antioxidant genes and lipid peroxidation in the liver of high cholesterol diet fed rats.…”