Quercetin Reduces Lipid Accumulation in a Cell Model of NAFLD by Inhibiting De Novo Fatty Acid Synthesis through the Acetyl-CoA Carboxylase 1/AMPK/PP2A Axis.

Antonio Gnoni,Fabrizio Damiano,Gabriele Vincenzo Gnoni,Luisa Siculella,Benedetta Di Chiara Stanca,Laura Giannotti

doi:10.3390/ijms23031044

Abstract

Dysregulation of de novo lipogenesis (DNL) has recently gained strong attention as being one of the critical factors that contribute to the assessment of non-alcoholic fatty liver disease (NAFLD). NAFLD is often diagnosed in patients with dyslipidemias and type 2 diabetes; thus, an interesting correlation can be deduced between high hematic free fatty acids and glucose excess in the DNL dysregulation. In the present study, we report that, in a cellular model of NAFLD, the coexistence of elevated glucose and FFA conditions caused the highest cellular lipid accumulation. Deepening the molecular mechanisms of the DNL dysregulation—RT-qPCR and immunoblot analysis demonstrated increased expression of mitochondrial citrate carrier (CiC), cytosolic acetyl-CoA carboxylase 1 (ACACA), and diacylglycerol acyltransferase 2 (DGAT2) involved in fatty acids and triglycerides synthesis, respectively. XBP-1, an endoplasmic reticulum stress marker, and SREBP-1 were the transcription factors connected to the DNL activation. Quercetin (Que), a flavonoid with strong antioxidant properties, and noticeably reduced the lipid accumulation and the expression of SREBP-1 and XBP-1, as well as of their lipogenic gene targets in steatotic cells. The anti-lipogenic action of Que mainly occurs through a strong phosphorylation of ACACA, which catalyzes the committing step in the DNL pathway. The high level of ACACA phosphorylation in Que-treated cells was explained by the intervention of AMPK together with the reduction of enzymatic activity of PP2A phosphatase. Overall, our findings highlight a direct anti-lipogenic effect of Que exerted through inhibition of the DNL pathway by acting on ACACA/AMPK/PP2A axis; thus, suggesting this flavonoid as a promising molecule for the NAFLD treatment.

Highlights

Since non-alcoholic fatty liver disease (NAFLD) is a disease associated with unbalanced diets, the first intervention to tackle this pathology is the adoption of a correct lifestyle and the intake of healthy diets, for example, the Mediterranean diet rich in unsaturated fatty acids and polyphenols
We found that the mRNA amount and the protein level for mitochondrial citrate carrier (CiC), acetyl-CoA carboxylase 1 (ACACA), and diacylglycerol mitochondrial citrate carrier (CiC), acetyl-CoA carboxylase 1 (ACACA), and diacylglycO-acyltransferase 2 (DGAT2) were remarkably augmented in cells incubated in high glucose (HG) and erol O-acyltransferase 2 (DGAT2) were remarkably augmented in cells incubated in HG
Since NAFLD is a disease associated with unbalanced diets, the first intervention to tackle this pathology is the adoption of a correct lifestyle and the intake of healthy diets, rich in fruits and vegetables, which are abundant in polyphenols, such as quercetin

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) represents a major global public health challenge and it is the most common chronic liver disease worldwide. It ranges from simple steatosis without specific inflammatory behaviors to more severe nonalcoholic steatohepatitis (NASH) and cirrhosis, with a seriously increased risk of developing hepatocellular carcinoma [1]. It was shown that de novo lipogenesis (DNL), i.e., the de novo synthesis of fatty acids from carbohydrate sources (mainly glucose), accounts for at least 35% of lipids present in steatotic cells [4,5] This aspect undoubtedly constitutes an evident paradoxical condition according to which new molecules of fatty acids are synthesized, while an abundance of lipids are available in steatotic cells

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