Anti-Hyperlipidemic Effects of Synthetic Analogs of Nordihydroguaiaretic acid (NDGA) in Dyslipidemic Rats.

OBJECTIVE

Previous studies have shown that Creosote bush-derived NDGA exerts beneficial actions on the key components of MetS including dyslipidemia, insulin resistance and hypertension in several relevant rodent models. Here we synthesized and screened a total of 6 antihyperlipidemic analogs of NDGA and tested their efficacy against hepatic lipid metabolism in a high-fructose diet (HFrD) fed dyslipidemic rat model.

METHODS

HFrD fed Sprague-Dawley (SD) treated with NDGA or one of the 6 analogs were used here. Serum samples were analyzed for blood metabolites, whereas liver samples were quantified for changes in various mRNA levels by real-time RT-PCR.

RESULTS

Oral gavage of HFrD-fed rats for 4 days with NDGA analogs 1 and 2 (100 mg/kg, once daily) suppressed the hepatic triglyceride content, whereas treatment of rats with NDGA analogs 2, 3 and 4, like NDGA, decreased the plasma triglyceride levels by 70-75%. qRT-PCR measurements demonstrated that among the NDGA analogs 1, 2, 4 and 5, analog 4 was most effective in inhibiting the mRNA levels of some key enzymes and transcription factors involved in lipogenesis. All four analogs almost equally inhibited the key genes involved in triglyceride synthesis and fatty acid elongation. Unlike NDGA, none of the analogs affected the genes of hepatic fatty acid oxidation or transport CONCLUSIONS AND IMPLICATIONS: Our data suggest that NDGA analogs 1, 2, 4 and 5, particularly analog 4, exert their anti-hyperlipidemic actions by negatively targeting genes of key enzymes and transcription factors involved in lipogenesis, triglyceride synthesis and fatty acid elongation. These analogs have therapeutic implications.