Prevention of free fatty acid-induced hepatic lipotoxicity by 18β-glycyrrhetinic acid through lysosomal and mitochondrial pathways

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and affects millions of people worldwide. Despite the increasing prevalence of NAFLD, the exact molecular/cellular mechanisms remain obscure and effective therapeutic strategies are still limited. It is well-accepted that free fatty acid (FFA)-induced lipotoxicity plays a pivotal role in the pathogenesis of NAFLD. Inhibition of FFA-associated hepatic toxicity represents a potential therapeutic strategy. Glycyrrhizin (GL), the major bioactive component of licorice root extract, has a variety of pharmacological properties including anti-inflammatory, antioxidant, and immune-modulating activities. GL has been used to treat hepatitis to reduce liver inflammation and hepatic injury; however, the mechanism underlying the antihepatic injury property of GL is still poorly understood. In this report, we provide evidence that 18 ␤-glycyrrhetinic acid (GA), the biologically active metabolite of GL, prevented FFA-induced lipid accumulation and cell apoptosis in in vitro HepG2 (human liver cell line) NAFLD models. GA also prevented high fat diet (HFD)-induced hepatic lipotoxicity and liver injury in in vivo rat NAFLD models. GA was found to stabilize lysosomal membranes, inhibit cathepsin B expression and enzyme activity, inhibit mitochondrial cytochrome c release, and reduce FFA-induced oxidative stress. These characteristics may represent major cellular mechanisms, which account for its protective effects on FFA/HFD-induced hepatic lipotoxicity. Conclusion: GA significantly reduced FFA/HFD-induced hepatic lipotoxicity by stabilizing the integrity of lysosomes and mitochondria and inhibiting cathepsin B expression and enzyme activity.

Prevention of Free Fatty Acid-Induced Hepatic Lipotoxicity in HepG2 Cells by Magnesium Isoglycyrrhizinate in vitro

“…All cells were plated in a cell culture flask at least 24 h before treatment. On reaching 70% confluence, the cultured cells were incubated with 1 mmol/l FFAs (oleic acid/palmitic acid, 2: 1) and MGL of different concentrations in media containing 1% FFA-free BSA as preciously described [7] . The raw MGL material was given by Jiangsu Chia-Tai Tianqing Pharmacy, and dissolved in serum-free medium to obtain a 20 mg/ml stock solution.…”

“…1 ). In our previous study, 18 ␤ -GA, a licorice compound, was proved to be protective in FFA-induced lipotoxicity, both in vivo and in vitro [7] . Magnesium isoglycyrrhizinate (MGL) is a novel compound of the ␣ -isomer synthesized from 18 ␤ -GL after isomerization and salification.…”

Sasa quelpaertensisandp-Coumaric Acid Attenuate Oleic Acid-Induced Lipid Accumulation in HepG2 Cells

“…10,12) Intracellular lipid accumulation is the main pathological characteristic of a human liver with NAFLD. 13) Free fatty acids (FFAs) are the main substrates of synthetic triglycerides (TGs) in hepatocytes. Excessive ingestion of fat and metabolic syndrome conditions, such as obesity, insulin resistance, and type 2 diabetes, can result in increased FFA levels in the blood.…”

Prevention of HIV Protease Inhibitor-Induced Dysregulation of Hepatic Lipid Metabolism by Raltegravir via Endoplasmic Reticulum Stress Signaling Pathways

“…To determine whether the protective effect of raltegravir on HIV PI-induced UPR activation is correlated to its effect on lipid homeostasis, we first examined the effect of raltegravir on lopinavir and ritonavir-induced lipid accumulation in hepatocytes. The intracellular lipid was stained using Nile red fluorescence dye as described previously (Wu et al, 2008). As shown in Fig.…”