ω3PUFAs improve hepatic steatosis in postnatal overfed rats and HepG2 cells by inhibiting acetyl-CoA carboxylase.

Nan Zhou,Xiaonan Li,Yanyan Dai,Susu Du,Fan Yang

doi:10.1002/fsn3.2482

Abstract

Postnatal overfeeding can lead to persistent increases in hepatic lipid synthesis and the risk of nonalcoholic fatty liver disease (NAFLD) in adulthood. The ω3 polyunsaturated fatty acids (ω3PUFAs) exhibit beneficial effects on NAFLD. Here, we employed a rat model and an in vitro HepG2 cell model to investigate whether fish oil (FO) affects hepatic lipid synthesis due to postnatal overfeeding. Male Sprague‐Dawley were divided into litter sizes of three (small litters, SLs) or 10 (normal litters, NLs) on postnatal day 3 and were fed standard chow or FO diet beginning on postnatal week 3 to generate NL, SL, NL‐FO, and SL‐FO groups. The results indicated that the FO diet reduced the postnatal overfeeding‐induced body weight gain and NAFLD characteristics (such as serum and liver triglyceride (TG) and hepatic steatosis). In addition, FO restored the expression of hepatic lipid metabolism‐related genes (including SCD1, FASN, CPT1, LPL, ACC, and SREBP‐1c) in SL‐FO rats. Specifically, the activity and expression pattern of ACC were consistent with SREBP‐1c. Furthermore, HepG2 cells were treated with oleic acid (OA), followed by eicosapentenoic acid (EPA), with or without SREBP‐1c siRNA. The cellular lipid droplets, TG content, and the expression of ACC (by 75%) and SREBP‐1c (by 45%) were increased by OA stimulation (p < .05), which was inhibited by EPA treatment. However, the effect of EPA treatment was abolished when SREBP‐1c was silenced. In conclusion, ω3PUFAs‐rich diet may be an effective way to reverse the developmental programming of hepatic lipid synthesis, at least partially, by inhibiting ACC through modulating SREBP‐1c.

Highlights

With the increasing prevalence of obese children, nonalcoholic fatty liver disease (NAFLD) has become one of the most common chronic liver diseases in pediatric population (Flisiak-Jackiewicz & Lebensztejn, 2019; Hales et al, 2017)
In order to determine whether the regulation of eicosapentenoic acid (EPA) on acetyl-CoA carboxylase (ACC) was mediated by SREBP-1c, we examined the mRNA expression of ACC
The most important finding was that postweaning ω3 polyunsaturated fatty acids (ω3PUFAs) diet prevented the weight gain and reduced the risk of NAFLD development by Small litter (SL) rearing

Summary

| INTRODUCTION

NAFLD is characterized by excessive triglyceride (TG) accumulation in the absence of significant alcohol consumption (Aguila, 2011) and is primarily caused by the imbalance in which lipid availability (uptake and synthesis) exceeds lipid disposal (oxidation and export; Kjaergaard et al, 2014; Musso et al, 2009) It is well-known that hepatic lipid metabolism, including circulating lipid uptake, de novo lipogenesis (DNL), fatty acid oxidation, and TG-rich lipoprotein secretion, is regulated by several rate-limiting enzymes and transcription factors(Kjaergaard et al, 2014). CPT1 and PPARα expressions decreased when insulin resistance occurred (Ji et al, 2014) All such observations indicate that the overnutritional in early life can affect the expression of those enzymes involved in hepatic lipid synthesis and reprogram such metabolic pathways in later life. This study focused on the effects of ω3PUFAs on hepatic lipid synthesis and the underlying molecular mechanisms in early life

| MATERIALS AND METHODS

| DISCUSSION