Nordihydroguaiaretic acid protects against high-fat diet-induced fatty liver by activating AMP-activated protein kinase in obese mice.
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.
Lee
Myoung-Su
MS
Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, 262 Seongsanno, Seodaemun-gu, Seoul 120-749, Republic of Korea.
Kim
Daeyoung
D
Jo
Keunae
K
Hwang
Jae-Kwan
JK
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
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