2-Heptyl-Formononetin Increases Cholesterol and Induces Hepatic Steatosis in Mice

Abstract

Consumption of isoflavones may prevent adiposity, hepatic steatosis, and dyslipidaemia. However, studies in the area are few and primarily with genistein. This study investigated the effects of formononetin and its synthetic analogue, 2-heptyl-formononetin (C7F), on lipid and cholesterol metabolism in C57BL/6J mice. The mice were fed a cholesterol-enriched diet for five weeks to induce hypercholesterolemia and were then fed either the cholesterol-enriched diet or the cholesterol-enriched diet-supplemented formononetin or C7F for three weeks. Body weight and composition, glucose homeostasis, and plasma lipids were compared. In another experiment, mice were fed the above diets for five weeks, and hepatic triglyceride accumulation and gene expression and histology of adipose tissue and liver were examined. Supplementation with C7F increased plasma HDL-cholesterol thereby increasing the plasma level of total cholesterol. Supplementation with formononetin did not affect plasma cholesterol but increased plasma triglycerides levels. Supplementation with formononetin and C7F induced hepatic steatosis. However, formononetin decreased markers of inflammation and liver injury. The development of hepatic steatosis was associated with deregulated expression of hepatic genes involved in lipid and lipoprotein metabolism. In conclusion, supplementation with formononetin and C7F to a cholesterol-enriched diet adversely affected lipid and lipoprotein metabolism in C57BL/6J mice.

Acute and sub-chronic oral toxicity studies of the leaves aqueous extract of Clerodendrum umbellatum Poir. on mice

“…In contrast, HDL-cholesterol tends to carry cholesterol away from the arteries to the liver. Thus, an increase in HDL-cholesterol protects against cardiovascular diseases [25,26]. This result showed that CuAE could have some beneficial effects by reducing cardiovascular risk factors.…”

Non-alcoholic Fatty Liver Disease: Beneficial Effects of Flavonoids

“…Likewise, a mixture of polyphenols, containing resveratrol, genistein, and quercetin, increased hepatic lipids but did not activate expression of genes relative to apoptosis, cell repair, or tissue remodeling (Miller et al, ). Also, formononetin, an O ‐methylated isoflavone, decreased liver weight, inflammation, and injury but simultaneously increased plasma triglyceride levels and caused hepatic steatosis (Andersen et al, ). As expected, hepatic steatosis was associated with downregulation of fatty acid β ‐oxidation genes ( Atgl , Cpt1a , Acox1 , and Acat2 ) and the microsomal triglyceride transfer protein, a gene that is responsible for lipoprotein assembly and export from the liver (Andersen et al, ).…”

“…Also, formononetin, an O ‐methylated isoflavone, decreased liver weight, inflammation, and injury but simultaneously increased plasma triglyceride levels and caused hepatic steatosis (Andersen et al, ). As expected, hepatic steatosis was associated with downregulation of fatty acid β ‐oxidation genes ( Atgl , Cpt1a , Acox1 , and Acat2 ) and the microsomal triglyceride transfer protein, a gene that is responsible for lipoprotein assembly and export from the liver (Andersen et al, ). Why in these studies isoflavones prevent hepatic inflammation and injury (i.e., NASH) without suppressing hepatic steatosis is not clear, but different signaling pathways that isoflavones interact with may be the reason.…”

Poly‐pharmacokinetic Study of a Multicomponent Herbal Medicine in Healthy Chinese Volunteers

“…Formononetin, another active compound of Radix Astragali, has been reported to be able to decrease markers of inflammation and liver injury in a cholesterol-enriched diet-induced hepatic steatosis C57BL/6J mice model. 36 Formononetin can be metabolized into formononetin glucuronide in the colon by uridine 5 0 -diphospho-glucuronosyl transferases (UGTs) 37 and, again, bacteria expressing high concentrations of glucuronidases can release formononetin from formononetin glucuronide to exert bioactive effects.…”