Lysosomal Acid Lipase, a Novel Biomarker for Hepatic Fibrosis

Abstract

Background: Hepatic fibrosis (HF) can be easily developed irreversible liver cirrhosis or even liver cancer. Lysosomal acid lipase (LAL), encoded by the lipase A (Lipa) gene, is a critical enzyme involved in cholesterol ester metabolism and is considered a biomarker for liver cirrhosis. However, the association between LAL and HF, as well as the role of LAL in HF development are poorly understood. In this study, we aimed to determine whether LAL served a novel biomarker for HF development and reveal its underlying mechanism. Methods: The expression of LAL was surveyed in the liver tissues of CCl 4 and high-fat diet (HFD)-induced HF animals. Alpha smooth muscle actin level, collagen and Gata family expression was analyzed by Real-time PCR and Western blot. The identification of putative transcription factor binding sites in the DNA sequences of Lipa was located by PROMO-ALGGEN v8.3 online software and ENCODE ChIP-Seq Significance Tool. MD simulation was performed using Desmond to explore the protein-ligand interaction. Findings: Our results showed that LAL expression was reduced in TGF-β1-induced HSC-T6 cells and liver tissues. Gata 3, a member in the Gata family that transcribes Lipa, was involved in the pathological process of HF. More importantly, morroniside, an active compound of Cornus officinalis Sieb. et Zucc., regulated the GATA3/Lipa axis, inhibited HSCs activation and enhanced extracellular matrix (ECM) degradation. These findings, for the first time, suggest a novel biomarker for HF, which is also a molecular target of morroniside for its anti-HF effects. Interpretation: This study provides strong scientific evidence to support the development of morroniside as novel alternative or complementary therapeutics for HF prevention and treatment. Funding: This work was supported by the Basic and Applied Basic Research Fund Project of Guangdong Province (NO.2019A1515110202), the China Postdoctoral Science Foundation (NO.2020M672604), The National Natural Science Foundation of China (82074019 and 81930114), Characteristic innovation projects of universities in Guangdong Province (2020KTSCX030), Guangdong Key Laboratory for Translational Cancer research of Chinese Medicine (2018B030322011), Key-Area Research and Development Program of Guangdong Province (No. 2020B1111100004). Research Grant Council of HKSAR (HKBU-22103017-ECS), Innovation & Technology Commission (PRP/015/19FX), National Natural Science Foundation of China (SCM-2016-NSFC-003) and Natural Science Foundation of Guangdong Province (2018A0303130122). Declaration of Interest: None to declare. Ethical Approval: All animals received humane care, and the experimental protocol was approved by the Committee of Laboratory Animals and was performed according to institutional guidelines.