LCAT protects against Lipoprotein‐X formation in a murine model of drug‐induced intrahepatic cholestasis

Abstract

Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is a rare genetic disease characterized by low HDL‐C levels, low plasma cholesterol esterification, and the formation of Lipoprotein‐X (Lp‐X), an abnormal cholesterol‐rich lipoprotein particle. LCAT deficiency causes corneal opacities, normochromic normocytic anemia, and progressive renal disease due to Lp‐X deposition in the glomeruli. Recombinant LCAT is being investigated as a potential therapy for this disorder. Several hepatic disorders, namely primary biliary cirrhosis, primary sclerosing cholangitis, cholestatic liver disease, and chronic alcoholism also develop Lp‐X, which may contribute to the complications of these disorders. We aimed to test the hypothesis that an increase in plasma LCAT could prevent the formation of Lp‐X in other diseases besides FLD. We generated a murine model of intrahepatic cholestasis in LCAT‐deficient (KO), wild type (WT), and LCAT‐transgenic (Tg) mice by gavaging mice with alpha‐naphthylisothiocyanate (ANIT), a drug well known to induce intrahepatic cholestasis. Three days after the treatment, all mice developed hyperbilirubinemia and elevated liver function markers (ALT, AST, Alkaline Phosphatase). The presence of high levels of LCAT in the LCAT‐Tg mice, however, prevented the formation of Lp‐X and other plasma lipid abnormalities in WT and LCAT‐KO mice. In addition, we demonstrated that multiple injections of recombinant human LCAT can prevent significant accumulation of Lp‐X after ANIT treatment in WT mice. In summary, LCAT can protect against the formation of Lp‐X in a murine model of cholestasis and thus recombinant LCAT could be a potential therapy to prevent the formation of Lp‐X in other diseases besides FLD.

Preclinical evidence of Yinchenhao decoction on cholestasis: A systematic review and meta‐analysisof animal studies

“…Bile duct epithelium releases pro‐inflammatory factors, leading to lipid peroxidation and damage to bile duct epithelium. Bile stored in the liver, component replication and increased concentration are the main causes of liver injury induced by apoptosis (Amar et al, 2019; Wang et al, 2019). FXR plays a central role in regulating BA synthesis, excretion and transport.…”

Lecithin:cholesterol acyltransferase: symposium on 50 years of biomedical research from its discovery to latest findings

“…Such findings support clinical evaluation of rhLCAT in patients with myocardial infarction and other cardiovascular diseases involving endothelial cell dysfunction. Similarly, recently published data using an animal model of chemically induced primary biliary cirrhosis suggests that rhLCAT treatment may be effective in reducing plasma LpX levels and reduce the risk for xanthoma formation, plasma hyperviscosity, and, perhaps, neuropathies in patients with primary biliary cirrhosis (40). Although more basic work is required to understand whether these beneficial effects of LCAT are exclusively due to its effects in improving HDL function or additional direct enzymatic effects in diseased tissues, rhLCAT therapy appears to be promising and the ongoing clinical studies may reveal new insights to guide patient selection and drug optimization and use.…”

Corrigendum

“…In Amar et al (2020), the article 1 was published with the following errors: In Fig. 3, standard HDL control in Lane 3 was mislabeled as baseline mouse plasma (m1). In Material and Methods section, subsection 2.2, the amount of rhLCAT given to the mice in Figures 6, 7 and SF3 was not clarified. …”