title: Prevention of free fatty acid-induced hepatic lipotoxicity by 18beta-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 beta-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.
  
  
  CONCLUSIONS
  GA significantly reduced FFA/HFD-induced hepatic lipotoxicity by stabilizing the integrity of lysosomes and mitochondria and inhibiting cathepsin B expression and enzyme activity.
authors.affiliation: Jiangsu Center for Drug Screening, Jiangsu Center for Pharmacodynamic Research and Evaluation, China Pharmaceutical University, Nanjing, Jiangsu, People's Republic of China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Wu
authors.forename: Luyong
authors.initials: L
authors.lastname: Zhang
authors.forename: Emily
authors.initials: E
authors.lastname: Gurley
authors.forename: Elaine
authors.initials: E
authors.lastname: Studer
authors.forename: Jing
authors.initials: J
authors.lastname: Shang
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Cuifen
authors.initials: C
authors.lastname: Wang
authors.forename: Ming
authors.initials: M
authors.lastname: Yan
authors.forename: Zhenzhou
authors.initials: Z
authors.lastname: Jiang
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Hylemon
authors.forename: Arun J
authors.initials: AJ
authors.lastname: Sanyal
authors.forename: William M
authors.initials: WM
authors.lastname: Pandak
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002401:Cathepsin B / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects; D004195:Disease Models, Animal; D005230:Fatty Acids, Nonesterified / Q000008:administration & dosage / Q000009:adverse effects*; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000893:Anti-Inflammatory Agents; D004041:Dietary Fats; D005230:Fatty Acids, Nonesterified; C119129:18alpha-glycyrrhetinic acid; D045304:Cytochromes c; D002401:Cathepsin B; D006034:Glycyrrhetinic Acid