(OR36-06-24) Sex-Specific Effects of Cocoa on Hepatic Redox Regulation and Lipid Homeostasis in High-Fat Diet-Fed Mice

Objectives: The rising incidence of nonalcoholic fatty liver disease (NAFLD) is a public health issue associated with the growing prevalence of obesity. Cocoa beans derived from Theobroma cacao L. are a rich dietary source of polyphenols. Previous studies have shown that dietary cocoa intervention can prevent obesity and NAFLD, but the relationship between sex and molecular mechanisms of action of cocoa in NAFLD remains unexplored. Our objective was to characterize the sex-dimorphic protective responses of cocoa in NAFLD pathogenesis in high-fat diet (HFD)-fed mice focusing on oxidative and endoplasmic reticulum (ER) stress.

Methods: Obese male and female C57BL/6J mice were randomized to HFD or HFD supplemented with unprocessed or differently fermented and/or roasted cocoa (80 mg/g). After 8 wks, mice were euthanized and markers of redox balance, ER stress, and lipid homeostasis were examined by quantitative reverse transcriptase polymerase chain reaction and western blot.

Results: Dietary supplementation with unprocessed or processed cocoa increased hepatic mitochondrial DNA copy number by 1.2-1.5 fold in male but not female mice. This was associated with an increase in nuclear respiratory factor 2 by 3-22 fold and mitochondrial transcription factor A mRNA expression by 2.8-4.5 fold in male mice. Unprocessed or processed cocoa intervention increased the expression of markers related to protein folding in the ER in males. ER oxidoreductin 1 and glutathione peroxidase 7 mRNA expression were increased in male mice. These were downregulated in female mice. We found that unprocessed or processed cocoa upregulated estrogen-related receptor α and its target genes (apolipoprotein B and microsomal triglyceride transfer protein) involved in hepatic lipid transport in female mice, but not in male mice.

Conclusions: In summary, we found that the dietary intervention of unprocessed or processed cocoa exerts protection against NAFLD in a sex-different manner. This understanding will support the development of efficacious approaches for NAFLD that take into account the heterogeneity in the population with obesity.

Funding Sources: This work was funded by USDA NIFA 2019-67017-29251 and 2017-67017-26783.