Pelargonic acid vanillylamide alleviates hepatic autophagy and ER stress in hepatic steatosis model

Naruemon Wikan; Jiraporn Tocharus; Chio Oka; Sivanan Sivasinprasasn; Waraluck Chaichompoo; Panida Denlumpai; Apichart Suksamrarn; Chainarong Tocharus

doi:10.1016/j.fct.2023.113987

Pelargonic acid vanillylamide alleviates hepatic autophagy and ER stress in hepatic steatosis model

Food Chem Toxicol. 2023 Oct:180:113987. doi: 10.1016/j.fct.2023.113987. Epub 2023 Aug 22.

Authors

Naruemon Wikan¹, Jiraporn Tocharus², Chio Oka³, Sivanan Sivasinprasasn¹, Waraluck Chaichompoo⁴, Panida Denlumpai⁴, Apichart Suksamrarn⁴, Chainarong Tocharus⁵

Affiliations

¹ Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
² Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
³ Laboratory of Functional Genomics and Medicine, Division of Biological Science, Nara Institute of Science and Technology, Nara, Japan.
⁴ Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, Thailand.
⁵ Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Center of Radiation Research and Medical Imaging, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand. Electronic address: chainarong.t@cmu.ac.th.

PMID: 37611858
DOI: 10.1016/j.fct.2023.113987

Abstract

Pelargonic acid vanillylamide (PAVA) has been shown to reduce hepatic lipid accumulation in an obese rat model, however the underlying mechanism responsible for regulating lipid metabolism remains unclear. This study investigated the molecular mechanisms invoked by PAVA in regulating lipogenesis, autophagy, and endoplasmic reticulum (ER) stress in obese rats. Male Sprague-Dawley rats were fed on a diet consisting of 65.26% fat (16 weeks) and HepG2 cells were incubated with 200 μM oleic acid (OA) plus 100 μM palmitic acid (PA) for 48 h. These treatments resulted in a steatosis model. PAVA was shown to reduce fat deposition in hepatocytes in HepG2 by reducing lipotoxicity, the triglyceride content, the expression of sterol regulatory element binding protein 1c (SREBP-1c) and fatty acid synthase (FASN). PAVA also significantly reduced the calcium level and the expression of calpain 2 and upregulated the expression of Atg7 in comparison to the HFD group. In addition, PAVA was shown to significantly decrease the expression of autophagy pathway-related proteins including LC3 and p62. Treatment with PAVA (1 mg/day) reduced the expressions of ER stress markers Bip, ATF6 (p50), p-IRE1/IRE1, p-eIF2α/eIF2α, pJNK, CHOP and cleaved CASP12. In conclusion, PAVA ameliorated obesity induced hepatic steatosis by attenuating defective autophagy and ER stress pathways.

Keywords: Autophagy; ER stress; Lipid accumulation; NAFLD; NASH; Nonivamide.