Decreased, PPARalpha transactivation of gene expression leads to Decreased, Mitochondrial Fatty Acid Beta Oxidation

PPARα is a transcriptional regulator for a variety of genes that facilitate systemic energy homeostasis (Kersten 2014, Evans et al 2004, Desvergne and Wahli 1999).  The KE “PPARalpha transactivation of gene expression, Decreased” results in the KE, “Mitochondrial Fatty Acid Beta Oxidation, Decreased” by inhibiting expression of the enzymes involved in mitochondrial fatty acid metabolism (Kersten 2014, Brandt et al. 1998; Mascaro et al. 1998, Aoyama et al. 1998, Gulick et al. 1994, Sanderson et al. 2008).  A robust literature-base is available for mitochondrial fatty acid beta-oxidation including broad investigation of key enzymes (Brandt et al. 1998; Mascaro et al. 1998, Kersten 2014, Sanderson et al. 2008, Aoyama et al. 1998) and detailed examination of metabolic flux (Aoyama et al. 1998, Badmann et al. 2007, Potthoff et al. 2009), thus the KER received relatively high scores (see weight of evidence section on main page https://aopkb.org/aopwiki/index.php/Aop:6).

Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?

A large body of research demonstrated that PPARα nuclear signaling directly controls transcriptional expression for genes catalyzing mitochondrial beta-oxidation of short, medium and long chain fatty acids (<20C) (as reviewed in Kersten 2014, Evans et al 2004, Desvergne and Wahli 1999, Sanderson et al 2010). The majority of the research described in these reviews was established using gene knock outs, so there is not much dose-response information available describing the KER between the KE, “decreased PPARα transactivation of gene expression” -> the KE “decreased mitochondrial fatty acid beta-oxidation”.

The relationships described herein have been primarily established in human and rodent models.