Prevention of free fatty acid-induced hepatic lipotoxicity by 18beta-glycyrrhetinic acid through lysosomal and mitochondrial pathways.
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.
Wu
Xudong
X
Jiangsu Center for Drug Screening, Jiangsu Center for Pharmacodynamic Research and Evaluation, China Pharmaceutical University, Nanjing, Jiangsu, People's Republic of China.
Zhang
Luyong
L
Gurley
Emily
E
Studer
Elaine
E
Shang
Jing
J
Wang
Tao
T
Wang
Cuifen
C
Yan
Ming
M
Jiang
Zhenzhou
Z
Hylemon
Phillip B
PB
Sanyal
Arun J
AJ
Pandak
William M
WM
Zhou
Huiping
H
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
D000893:Anti-Inflammatory Agents; D004041:Dietary Fats; D005230:Fatty Acids, Nonesterified; C119129:18alpha-glycyrrhetinic acid; D045304:Cytochromes c; D002401:Cathepsin B; D006034:Glycyrrhetinic Acid