Olvanil Reduces Subcutaneous Fat Accumulation and Lipogenic Gene Expression, Without Alleviating Hepatic Oxidative Stress or Histopathological Alterations in Mice with Metabolic Dysfunction-Associated Steatotic Liver Disease

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by excess intrahepatic lipid accumulation due to lipid overflow and synthesis, as well as impaired lipid oxidation. Olvanil (OLV) is a nonpungent capsaicin analog that has previously been shown to have anti-obesity effects in diet-induced obesity models. Nevertheless, its effects on fatty liver remain unclear. In this study, we evaluated the potential of OLV to address lipid metabolic dysfunction and MASLD-related hepatic abnormalities. C57BL/6 mice were fed a high-fat/high-fructose diet for 24 weeks, with or without OLV (25 mg/kg/day) administered by oral gavage for the last 8 weeks. We primarily evaluated the effects of OLV on liver function markers and the hepatic expression of key genes involved in lipid metabolism to assess its potential in reducing MASLD progression. We confirmed that OLV promoted lipolysis in adipocytes and significantly reduced body weight gain and fat accumulation, particularly in subcutaneous adipose tissue. At the molecular level, we demonstrated that OLV reduced the expression of lipogenic genes ( ACC, FASN, SREBP-1c, and PPAR-γ ). However, we observed elevated serum alanine aminotransferase levels and increased interleukin-6 and thiobarbituric acid reactive substances levels in liver tissue. Moreover, histopathological alterations such as hepatic steatosis and lobular inflammation tended to be more pronounced in OLV-treated animals than in untreated MASLD animals. In conclusion, while OLV reduced subcutaneous adiposity and liver lipogenic gene expression, it did not improve hepatic oxidative stress or histopathological alterations in a murine MASLD model. Free fatty acid-mediated lipotoxicity may be present, exacerbating hepatic oxidative stress and inflammatory changes; therefore, further studies are needed to confirm the proposed metabolic pathway.