PPARs in Rhythmic Metabolic Regulation and Implications in Health and Disease

Figure 1

Regulatory networks of the core clock components and PPARs. (1) Bmal1 is acetylated by CLOCK which possesses acetyltransferase activity. This process can be reversed by SIRT1 deacetylase activity. Acetylated Bmal1 and CLOCK proteins heterodimerize (2) translocate into nucleus and activate transcription of Per, Cry (3), and Rev-erbα (4). In turn, Per and Cry form a repression complex which, upon translocation from the cytoplasm into the nucleus, inhibits transcription driven by CLOCK/Bmal1, including its own, constituting the main feedback loop. Bmal1 expression is controlled by Rev-erbα and RORα, the two primary players in the secondary loop, in an opposing manner. Upon binding to a common RORE, Rev-erbα suppresses transcription (12) while RORα exerts transcriptional activation of Bmal1 (8). The expression of Rev-erbα is driven by CLOCK/Bmal1 (4) and RORα (5) and suppressed by itself (6). PPARs and the core clock proteins reciprocally regulate each other. PPARs regulate the transcription of some clock genes, for example, PPARα activates Rev-erbα (7) and Bmal1 (9) while PPAR𝛾 only activates Bmal1 transcription (9). On the other hand, clock genes regulate expression levels of PPARs. CLOCK/Bmal1 drives PPARα expression (10) and Rev-erbα activates transcription of mir-122 (11), a microRNA which downregulates expression of PPARβ/δ posttranscriptionally.