Oxysterol 7α-hydroxylase (CYP7B1) controls the levels of intracellular regulatory
oxysterols generated by the "acidic pathway" of
cholesterol metabolism. Previously, we demonstrated that an inability to upregulate CYP7B1 in the setting of
insulin resistance leads to the accumulation of
cholesterol metabolites such as (25R)26-hydroxycholesterol (26HC) that initiate and promote hepatocyte injury; followed by an inflammatory response. The current study demonstrates that dietary
coffee improves
insulin resistance and restores Cyp7b1 levels in a well-characterized Western diet (WD)-induced
nonalcoholic fatty liver disease (
NAFLD) mouse model. Ingestion of a WD containing caffeinated (regular)
coffee or decaffeinated
coffee markedly reduced the serum ALT level and improved
insulin resistance. Cyp7b1
mRNA and
protein levels were preserved at normal levels in mice fed the
coffee containing WD. Additionally,
coffee led to upregulated
steroid sulfotransferase 2b1 (Sult2b1)
mRNA expression. In accordance with the response in these
oxysterol metabolic genes, hepatocellular 26HC levels were maintained at physiologically low levels. Moreover, the current study provided evidence that hepatic Cyp7b1 and Sult2b1 responses to
insulin signaling can be mediated through a transcriptional
factor, hepatocyte nuclear factor (HNF)-4α. We conclude
coffee achieves its beneficial effects through the modulation of
insulin resistance. Both decaffeinated and caffeinated
coffee had beneficial effects, demonstrating
caffeine is not fundamental to this effect. The effects of
coffee feeding on the insulin-HNF4α-Cyp7b1 signaling pathway, whose dysregulation initiates and contributes to the onset and progression of NASH as triggered by
insulin resistance, offer mechanistic insight into approaches for the treatment of
NAFLD.NEW & NOTEWORTHY This study demonstrated dietary
coffee prevented the accumulation of hepatic
oxysterols by maintaining Cyp7b1/Sult2b1 expression in a diet-induced
NAFLD mice model. Lowering liver
oxysterols markedly reduced
inflammation in the
coffee-ingested mice.
Caffeine is not fundamental to this effect. In addition, this study showed Cyp7b1/Sult2b1 responses to
insulin signaling can be mediated through a transcriptional factor, HNF4α. The
insulin-HNF4α-Cyp7b1/Sult2b1 signaling pathway, which directly correlates to the onset of NASH triggered by
insulin resistance, offers insight into approaches for
NAFLD treatment.