The Western diet is an established risk factor for atherosclerosis due to substantial impact of saturated fat and cholesterol intake on the body's cholesterol homeostasis. An average American diet contains 37% of calories from fat and 385 mg/day of cholesterol, predominantly derived from animal sources. Significant advances have been made in defining transcription factors responding to either fatty acids or cholesterol, but whether there is a separate sensing mechanism in the body for detecting both fat and cholesterol is unknown. In particular, the nature and timing of dietary signals that can sense, integrate and synchronize cholesterol regulatory network in response to a high-fat/cholesterol load have not been studied. In view of recent demonstrations that dietary fat and dietary cholesterol act synergistically to impair cholesterol homeostasis, assessing the impact of both on dysregulated cholesterol homeostasis, rather than an individual component alone, is more physiologically relevant. We propose that the body has a separate sensor to detect both fat and cholesterol and utilize a distinct strategy for adaptation to high-fat/cholesterol load to minimize its detrimental impact on cholesterol homeostasis. Emerging evidence from our laboratory indicates that diet-sensitive PKC? is a critical link between high-fat/cholesterol intake and hepatic adaptiveness of cholesterol homeostasis. Consistent with this function, a high-fat/cholesterol diet dramatically induced PKC? expression in the liver, while a systemic PKC? deficiency elevated liver and plasma cholesterol content in response to high-fat/cholesterol diet. We suggested a molecular mechanism by which liver PKC? signaling, with or without ileum PKC?, converges on the liver Erk- 1/2 to differentially regulate critical transcription factors of cholesterol homeostasis. These observations are exciting in that they not only represent first demonstration of the role of a specific PKC isoform in cholesterol metabolism but may also provide a missing signaling and regulatory link between dietary lipids and cholesterol homeostasis. Based on the above results, we propose a novel hypothesis that PKC? is a ?fat/cholesterol sensor? whose activation in the liver represents a potent defense mechanism to cope with dietary high- fat/cholesterol insult by promoting cholesterol catabolism and concurrently downregulating cholesterol biosynthesis and uptake with the primary aim of avoiding over-accumulation of toxic cholesterol in the liver. PKC? thus represents a unique hub within the cholesterol homeostatic network. To test this hypothesis, we plan to use newly generated tissue-specific PKC? deficient mice to determine the impact of a liver-specific PKC? deficiency on diet-induced cholesterol homeostasis. After establishing its role, we plan to define the signaling and transcriptional mechanisms operating during diet-dependent liver PKC? induction. Finally, we propose to delineate the mechanism for requirement of PKC? in sterol-sensitive Srebp-2 processing. Establishing PKC? as a crucial checkpoint will provide novel targets for treating cholesterol diseases by unlocking this evolutionary developed endogenous mechanism to restore cholesterol homeostasis.

Public Health Relevance

Western diet enriched with high fat and high cholesterol is an established risk factor for the development of atherosclerosis and liver diseases. Significant advances have made in unraveling details and functions of transcription factors responsive to fat, cholesterol, or bile acids, but what is lacking is the knowledge of the sensor that detects combined load of fat, cholesterol and/or bile acid to regulate cholesterol homeostatic network accordingly. The goal of this investigation is to define a central mechanism which body employs to sense combined dietary load of fat/cholesterol and restore cholesterol homeostasis through differential regulation of transcription factors critical for cholesterol uptake, biosynthesis and catabolism.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
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Liu, Lijuan
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Ohio State University
Schools of Medicine
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Huang, Wei; Mehta, Devina; Sif, Said et al. (2017) Dietary fat/cholesterol-sensitive PKC?-RB signaling: Potential role in NASH/HCC axis. Oncotarget 8:73757-73765