Peroxisome Proliferator-Activated Receptor-α: A Pivotal Regulator of the Gastrointestinal Tract

Abstract

Peroxisome proliferator-activated receptor (PPAR)-α is a ligand-activated transcription factor distributed in various tissues and cells. It regulates lipid metabolism and plays vital roles in the pathology of the cardiovascular system. However, its roles in the gastrointestinal tract (GIT) are relatively less known. In this review, after summarizing the expression profile of PPAR-α in the GIT, we analyzed its functions in the GIT, including physiological control of the lipid metabolism and pathologic mediation in the progress of inflammation. The mechanism of this regulation could be achieved <i>via</i> interactions with gut microbes and further impact the maintenance of body circadian rhythms and the secretion of nitric oxide. These are also targets of PPAR-α and are well-described in this review. In addition, we also highlighted the potential use of PPAR-α in treating GIT diseases and the inadequacy of clinical trials in this field.

Keywords: disorder; gastrointestinal diseases; metabolism; peroxisome proliferator–activated receptor (PPAR)-α; transcription.

FIGURE 1

Model diagram of PPAR-α-regulating gene expression and multiple physiological processes in the gut. (A) Multiple types of fatty acid transporters are found on the surface of gastrointestinal epithelial cells, and most of their synthesis requires the activation of PPAR-α. (B) Other proteins maintaining the homeostasis of GIT are also regulated by PPAR-α, such as ZO-1 for gut permeability. (C) PPAR-α also regulates the expression of CHOP, which is responsible for regulating the endoplasmic reticulum stress (ERS).

FIGURE 2

Diagram of the PPAR-α–mediated inflammatory process and the regulation of circadian rhythms or circadian clock and satiety in the gut. (A) In many gastrointestinal diseases, PPAR-α is activated and initiates the expression of multiple anti-inflammation mediators, including ICAM-1 in vascular epithelial cells and IL-22 in NKp46⁺ ILC3 cells. These effects help reverse the imbalance of the T-cell number and maintain the homeostasis of the GIT. (B) Apart from its role in regulating the inflammatory process, PPAR-α could also affect the circadian rhythms or circadian clock (via the regulation of the c-Jun expression) and satiety (by controlling the secretion of NO, as mentioned in the main body of the review, and Figure 3 and Table 3 are referred for detailed information) in the body. Studies have demonstrated its close relation with NO and dopamine, while the detailed mechanism remains to be elucidated.

FIGURE 3

Pattern diagram of PPAR-α involved in TLRs and NOD2 on gastrointestinal circadian rhythms or circadian clock. Studies have found that gastrointestinal circadian rhythms or circadian clock is affected by the gut flora, which is mainly sensed via TLRs and NOD2. This stimulation is further detected by the c-Jun N-terminal kinase (JNK) and binds to the enhancer heptamer motif, resulting in the activation of PPAR-α and, in turn, activating the transcription of Bmal and Clock, which exert a direct impact on the regulation of gastrointestinal circadian rhythms or circadian clock.