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

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSION: These findings highlight the importance of dietary interventions during critical developmental windows and suggest ER stress inhibition as a promising therapeutic approach for NAFLD.