Abstract
Previous studies indicated that increased hepatic pescadillo 1 (PES1) in type II diabetic
mice was associated with lipid dysregulation. However, the role of PES1 in obesity-associated
lipid dysregulation is still unknown. This study investigates the effects and underlying
mechanism. Livers from obese and healthy humans and mice were collected, and C57BL/6J
mice were either fed on standard diet or high fat diet (HFD). McArdle 7777 rat hepatoma
cells were treated with phosphate-buffered saline and oleic acid (OA)+ palmitic acid
(PA), respectively. In vitro Pes1 knockdown or overexpression and in vivo Pes1 knockdown or liver-specific ablation or supplementation of Pes1 were used to explore the modulating role of PES1. We found that obesity in humans
enhanced hepatic PES1 protein, accompanied by increased plasma TG. These data are
consistent with those from OA+PA-treated cells and from HFD- or Pes1 overexpression-treated C57BL/6J mice. In vitro and in vivo Pes1 knockdown in cultured cells and in ob/ob mice promoted the expression of autophagy markers (TFEB, Beclin1 and LC3B-Ⅱ) while
decreasing p62 and TG, contrary to Pes1 overexpression in cells and in normal mice. Moreover, liver-specific knockout of
Pes1 protected the mice fed on HFD from increased TG levels, facilitating the TFEB, Beclin1
and LC3B-Ⅱ and curbing p62. Mechanistically, OA+PA increased C/EBPβ binding to the
Pes1 promoter, leading to the elevation of PES1, and subsequently enhancing PES1-facilitated
ubiquitination of TFEB. Our findings reveal that overexpression of hepatic PES1 in
obesity may induce TG dysregulation by inhibiting autophagy.
Abbreviations:
AAV9 (adeno-associated virus 9), ALT (alanine aminotransferase), ANOVA (analysis of variance), AST (aspartate aminotransferase), AUC (area-under curve), BMI (body mass index), BP (blood pressure), C/EBPβ (CCAAT enhancer binding protein β), ChIP (chromatin immunoprecipitation), CKO (conditional knockout), co-IP (co-immunoprecipitation), FFA (free fatty acid), FPG (fasting plasma glucose), GTT (glucose tolerance test), GWAS (genome-wide association studies), HDL-C (high-density lipoprotein cholesterol), H&E (hematoxylin-eosin), HFD (high fat diet), ITT (insulin tolerance test), LAMP1 (lysosomal associated membrane protein 1), LDL-C (low-density lipoprotein cholesterol), OA (oleic acid), PA (palmitic acid), PBS (phosphate-buffered saline), PES1 (pescadillo 1), qRT-PCR (quantitative real-time PCR), T2DM (type 2 diabetes mellitus), TC (total cholesterol), TFEB (transcription factor EB), TG (triglycerides), UA (uric acid)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: February 09, 2023
Accepted:
February 3,
2023
Received in revised form:
February 1,
2023
Received:
February 17,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 Elsevier Inc. All rights reserved.
