4-phenylbutyric acid attenuates hepatic ER stress, pyroptosis, and NAFLD in adult rat offspring exposed to a high-fat, high-fructose diet during perinatal and adulthood

Perinatal exposure to high-fat and/or high-fructose diets affects offspring metabolic programming, increasing the risk of metabolic disorders such as non-alcoholic fatty liver disease (NAFLD). In addition, re-exposure to these diets during adulthood exacerbates metabolic disturbances, indicating an interaction between early- and later-life diets in disease development. Therefore, the present study was designed to assess the effects of high-fat, high-fructose (HFF) diet exposure during the perinatal period and adulthood on hepatic endoplasmic reticulum (ER) stress, pyroptosis, and NAFLD development, as well as to evaluate the potential therapeutic effects of 4-phenylbutyric acid (4-PBA). Male rat offspring were randomly assigned to six groups based on perinatal and adulthood diets: normal diet during both periods (N-N), normal perinatal diet with adulthood HFF diet (N-HFF), perinatal HFF diet with normal adulthood diet (HFF-N), perinatal and adulthood HFF diet (HFF-HFF), perinatal and adulthood HFF diet with DMSO treatment (HFF-HFF-DMSO), and perinatal and adulthood HFF diet with 4-PBA treatment (HFF-HFF-4PBA). Metabolic parameters, inflammatory markers, oxidative and ER stress indicators, a pyroptosis marker, and hepatic histological parameters were evaluated. Exposure to the HFF diet during the perinatal period and adulthood induced insulin resistance, dyslipidemia, hepatic oxidative and ER stress, inflammation, pyroptosis, lipid droplet accumulation, and NAFLD development. Treatment with 4-PBA improved all adverse effects caused by HFF diet exposure during both the perinatal and adult periods in offspring. These findings highlight the importance of dietary interventions during critical developmental windows and suggest ER stress inhibition as a promising therapeutic approach for NAFLD.