Mutual Inhibitory Mechanisms between PPAR? and Hif-1?: Implication in Pulmonary Hypertension

Transcription factor hypoxia-inducible factor 1? (Hif-1?) is known for its crucial role in promoting the pathogenesis of pulmonary hypertension (PH). Previous studies have indicated the in-depth mechanisms that Hif-1? increases the distal pulmonary arterial (PA) pressure and vascular remodeling by triggering the intracellular calcium homeostasis, especially the store-operated calcium entry (SOCE) process. In our recent research paper published in the Journal of Molecular Medicine, we found that the transcription factor peroxisome proliferator-activated receptor ? (PPAR?) activation could attenuate the PH pathogenesis by suppressing the elevated distal PA pressure and vascular remodeling. Moreover, these effects are likely mediated through the inhibition of SOCE by suppressing Hif-1?. These results provided convincing evidence and novel mechanisms in supporting the protective roles of PPAR? on PH treatment. Then, by using comprehensive loss-of-function and gain-of-function strategies, we further identified the presence of a mutual inhibitory mechanism between PPAR? and Hif-1?. Basically, under chronic hypoxic stress, accumulated Hif-1? leads to abolished expression of PPAR? and progressive imbalance between PPAR? and Hif-1?, which promotes the PH progression; however, targeted PPAR? restoration approach reversely inhibits Hif-1? level and Hif-1? mediated signaling transduction, which subsequently attenuates the elevated pulmonary arterial pressure and vascular remodeling under PH pathogenesis

Hepatic E4BP4 induction promotes lipid accumulation by suppressing AMPK signaling in response to chemical or diet- induced ER stress

Prolonged ER stress has been known to be one of the major drivers of impaired lipid homeostasis during the pathogenesis of non- alcoholic liver disease (NAFLD). However, the downstream mediators of ER stress pathway in promoting lipid accumulation remain poorly understood. Here, we present data showing the b- ZIP transcription factor E4BP4 in both the hepatocytes and the mouse liver is potently induced by the chemical ER stress inducer tunicamycin or by high- fat, low- methionine, and choline- deficient (HFLMCD) diet. We showed that such an induction is partially dependent on CHOP, a known mediator of ER stress and requires the E- box element of the E4bp4 promoter. Tunicamycin promotes the lipid droplet formation and alters lipid metabolic gene expression in primary mouse hepatocytes from E4bp4flox/flox but not E4bp4 liver- specific KO (E4bp4- LKO) mice. Compared with E4bp4flox/flox mice, E4bp4- LKO female mice exhibit reduced liver lipid accumulation and partially improved liver function after 10- week HFLMCD diet feeding. Mechanistically, we observed elevated AMPK activity and the AMPKβ1 abundance in the liver of E4bp4- LKO mice. We have evidence supporting that E4BP4 may suppress the AMPK activity via promoting the AMPKβ1 ubiquitination and degradation. Furthermore, acute depletion of the Ampkβ1 subunit restores lipid droplet formation in E4bp4- LKO primary mouse hepatocytes. Our study highlighted hepatic E4BP4 as a key factor linking ER stress and lipid accumulation in the liver. Targeting E4BP4 in the liver may be a novel therapeutic avenue for treating NAFLD.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162728/3/fsb220918_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162728/2/fsb220918-sup-0001-FigS1-S10.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162728/1/fsb220918.pd