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Background & Aims: Dietary factors are likely an important determinant of gallstone development, and difficulty in adapting to lithogenic diets may predispose individuals to gallstone formation. Identification of the critical early diet-dependent metabolic markers of adaptability is urgently needed to prevent gallstone development. We focus on the interaction between diet and genes, and the resulting potential to influence gallstone risk by dietary modification., Methods: Expression levels of hepatic protein kinase C (PKC) isoforms were determined in lithogenic diet-fed mice, and the relationship of hepatic cholesterol content and PKCβ expression and the effect of hepatic PKCβ overexpression on intracellular signaling pathways were analyzed., Results: Lithogenic diet feeding resulted in a striking induction of hepatic PKCβ and PKCδ mRNA and protein levels, which preceded the appearance of biliary cholesterol crystals. Unlike PKCβ deficiency, global PKCδ deficiency did not influence lithogenic diet-induced gallstone formation. Interestingly, a deficiency of apolipoprotein E abrogated the diet-induced hepatic PKCβ expression, whereas a deficiency of liver X receptor-α further potentiated the induction, suggesting a potential link between the degree of hepatic PKCβ induction and the intracellular cholesterol content. Furthermore, our results suggest that PKCβ is a physiologic repressor of ileum basal fibroblast growth factor 15 (FGF15) expression and activity of hepatic proto-oncogene serine/threonine-protein kinase Raf-1/mitogen-activated protein (MAP) kinase kinase/extracellular signal-regulated kinases 1/2 (Raf-1/MEK/ERK1/2) cascade proteins, and the complex interactions between these pathways may determine the degree of hepatic ERK1/2 activation, a potent suppressor of cholesterol 7α-hydroxylase and sterol 12α-hydroxylase expression. We found that PKCβ regulated Raf-1 activity by modulating the inhibitory Raf-1 Ser259 phosphorylation., Conclusions: Our results demonstrate a novel interaction between the hepatic PKCβ/Raf-1 regulatory axis and ileum PKCβ/FGF15/ERK axis, which could modulate the bile lithogenecity of dietary lipids. The data presented are consistent with a two-pronged mechanism by which intestine and liver PKCβ signaling converges on the liver ERK1/2 pathway to control the hepatic adaptive response to a lithogenic diet. Elucidating the impact and the underlying mechanism(s) of PKCβ action could help us understand how different types of dietary fat modify the risk of gallstone formation, information that could help to identify novel targets for therapeutic approaches to combat this disease.