Hexaraphane Affects the Activation of Hepatic PPARα Signaling: Impact on Plasma Triglyceride Levels and Hepatic Senescence with Aging

Background/Objectives: Hexaraphane, also known as 6-methylsulfinylhexyl isothiocyanate, derived from wasabi (Eutrema japonicum), increases heme oxygenase-1 (HO-1) and aldehyde dehydrogenase 2 (ALDH2) mRNA expression by activating nuclear factor erythroid 2-related factor 2 (Nrf2) in both HepG2 cells and the mouse liver. Given the presence of a peroxisome proliferator-activated receptor (PPAR) response element (PPRE) in the HO-1 and ALDH2 promoters, the present study aimed to determine the effects of hexaraphane on PPARα-associated genes, age-related weight gain, plasma triglyceride levels, and hepatic senescence. Methods: HepG2 cells were treated with hexaraphane to evaluate PPARα target gene expression and PPRE transcriptional activity. Male C57BL/6J young control, aged control, and aged mice administered with hexaraphane for 16 weeks were assessed for food and water intake, body and tissue weights, plasma parameters, and hepatic PPARα-related gene expression. Results: Hexaraphane increased HO-1 mRNA expression levels in HepG2 cells, which was inhibited by GW6471, a PPARα antagonist. It elevated PPRE transcriptional activity and increased carnitine palmitoyltransferase 1A (CPT1A) mRNA expression levels, indicating PPARα activation. In aged mice, hexaraphane intake reduced body weight gain by decreasing the adipose tissue weight. Increased CPT1A expression levels and a tendency toward increased acyl-CoA oxidase 1 (ACOX1) expression levels in the liver of aged mice administered hexaraphane were associated with reduced plasma triglyceride levels and body weight gain. Increased hepatic Sirt1 expression levels in aged mice administered hexaraphane was associated with lower plasma triglyceride levels. Increased hepatic PPARα mRNA expression levels in aged mice administered hexaraphane suggest a positive feedback loop between PPARα and Sirt1. The expression levels of hepatic p21 mRNA, a senescence marker regulated by Sirt1, were upregulated in aged mice but suppressed by hexaraphane intake. Conclusions: Hexaraphane may prevent age-related body weight gain, elevated plasma triglyceride levels, and hepatic senescence by activating PPARα, potentially contributing to longevity.