title: Nordihydroguaiaretic acid protects against high-fat diet-induced fatty liver by activating AMP-activated protein kinase in obese mice.
abstract: Nonalcoholic fatty liver disease, one of the most common causes of chronic liver disease, is strongly associated with metabolic syndrome. Nordihydroguaiaretic acid (NDGA) has been reported to inhibit lipoprotein lipase; however, the effect of NDGA on hepatic lipid metabolism remains unclear. We evaluated body weight, adiposity, liver histology, and hepatic triglyceride content in high-fat diet (HFD)-fed C57BL/6J mice treated with NDGA. In addition, we characterized the underlying mechanism of NDGA's effects in HepG2 hepatocytes by Western blot and RT-PCR analysis. NDGA (100 or 200mg/kg/day) reduced weight gain, fat pad mass, and hepatic triglyceride accumulation, and improved serum lipid parameters in mice fed a HFD for 8 weeks. NDGA significantly increased AMP-activated protein kinase (AMPK) phosphorylation in the liver and in HepG2 hepatocytes. NDGA downregulated the level of mature SREBP-1 and its target genes (acetyl-CoA carboxylase and fatty acid synthase), but, it upregulated expression of genes involved in fatty acid oxidation, such as peroxisome proliferator-activated receptor (PPAR)α, PPARγ coactivator-1, carnitine palmitoyl transferase-1, and uncoupling protein-2. The specific AMPK inhibitor compound C attenuated the effects of NDGA on expression of lipid metabolism-related proteins in HepG2 hepatocytes. The beneficial effects of NDGA on HFD-induced hepatic triglyceride accumulation are mediated through AMPK signaling pathways, suggesting a potential target for preventing NAFLD.
authors.affiliation: Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, 262 Seongsanno, Seodaemun-gu, Seoul 120-749, Republic of Korea.
authors.forename: Myoung-Su
authors.initials: MS
authors.lastname: Lee
authors.forename: Daeyoung
authors.initials: D
authors.lastname: Kim
authors.forename: Keunae
authors.initials: K
authors.lastname: Jo
authors.forename: Jae-Kwan
authors.initials: JK
authors.lastname: Hwang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D004032:Diet / Q000009:adverse effects; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism; D005234:Fatty Liver / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage*; D008297:Male; D009637:Masoprocol / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D014280:Triglycerides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects
chemical_list: D004041:Dietary Fats; D007328:Insulin; D016859:Lipoxygenase Inhibitors; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D014280:Triglycerides; C516138:dorsomorphin; D009637:Masoprocol; D055372:AMP-Activated Protein Kinases