Anthocyanins reduce inflammation and improve glucose and lipid metabolism associated with inhibiting nuclear factor-kappaB activation and increasing PPAR-γ gene expression in metabolic syndrome subjects

Highlights

• Anthocyanins improve FBG & lipid profile by up-regulating PPRAG mRNA.

• Anthocyanins significantly decrease NF-kB dependent gene activation.

• Anthocyanins inhibit TNF-α and COX-2 expressions and IL-6 production.

• Anthocyanins improved selected features of cardiometabolic risk factors.

Abstract

Anthocyanins exhibit antioxidant and anti-inflammatory activities via a multitude of biochemical mechanisms. However, the signaling pathways involved in the actions of anthocyanins against chronic inflammation are not fully understood.

The effects of berry-rich anthocyanin supplements (320 mg/day) for four weeks were examined on features of metabolic syndrome components and the expression of PPAR-γ, Nrf2, and NF-κB dependent genes in MetS and healthy subjects. Total RNA was isolated from whole blood with the PAXgene proprietary blood collection system.

Four weeks anthocyanin consumption significantly decreased fasting blood glucose (15.7% vs 3.2%), TG (18.2% vs -1.39%), cholesterol (33.5% vs 1.56%) and LDL (28.4% vs -15.6%) in the MetS compared to Control group (P-value < 0.05, 95% CI). There was a significant up regulation in the expression PPAR-γ gene associated with the lipid and glucose metabolism in MetS subjects which negatively correlated (P-value < 0.01) with the change in the FBG (r = -0.488), Cholesterol (r = -0.496), TG (r = -0.513) and LDL (r = -0.519). Moreover, anthocyanin supplementation decreases serum hs-CRP (-36.3% vs 6.25%) in MetS in compared to Control group (P-value < 0.05). Anthocyanin supplementation also down-regulated the expression of NF-κB dependent genes including TNF-α (-28% and -15%), IL-6 (-16.1% and -13.6%), IL-1A (-21.5% and -12.9%), PCAM-1 (-15% and -17.5%), and COX-2(-26% and -27%) in both MetS and Control group respectively (P-value < 0.05).

The study results suggested that berry supplements improved selected features of metabolic syndrome and related cardiovascular risk factors. These benefits may be due to the inhibition of NF-κB dependent gene expression and enhancement of PPAR-γ.

Introduction

Metabolic syndrome (MetS) has become a leading health concern due to its link to cardiovascular disease (CVD) [1]. The prevalence of MetS and CVD is expected to rise due to the global obesity epidemic [2]. The main diagnostic components of MetS are identified with reduced HDL-cholesterol, raised triglycerides, blood pressure, and fasting plasma glucose, all of which are related to weight gain, specifically abdominal fat accumulation [3]. Reducing levels of modifiable atherogenic risk factors is an essential goal in the prevention of CVD in metabolic syndrome populations. There is an established relationship between metabolic syndrome, oxidative stress, chronic inflammation, and cardiovascular disease [4]. The pathogenesis of atherosclerotic plaque formation is a multiphase process, including the interaction between immune cells and endothelium [5].

Currently, there is much interest in phytochemicals as bioactive components of food [6]. The roles of fruit and vegetables in disease prevention have been attributed in part to their antioxidant properties [7]. Recent studies have indicated that dietary polyphenolic constituents derived from plants are effective antioxidants in vitro and, as a result, might contribute significantly to the protective effects in vivo [[7], [8], [9]]. Anthocyanins, a category of polyphenolic pigments belong to the flavonoid group, are responsible for a variety of colors present in the plant from red-orange to blue-violet in fruits, flowers, and leaves [10]. The epidemiological study demonstrated that higher consumption of anthocyanin extracts or anthocyanin-rich fruit was attributed to improved cardiovascular risk profile [11]. Results from mechanistic studies suggest that anthocyanin ability to lower CVD risk mediate through the regulation expression of proinflammatory genes and reducing the production of anti-inflammatory molecules [12,13]. Anthocyanins decrease iNOS activity and, consequently, nitric oxide overexpression [14] and attenuate COX-2 activity and accordingly, PGE2 expression [15,16]. Due to their mechanisms of action, plenty of the evidence points to the involvement of the nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and Peroxisome proliferator-activated receptors (PPARs) pathways. However, so far, no human studies have systematically investigated the metabolic effect of purified anthocyanin on gene dependent expression of Nrf2, NF-κB and PPAR-γ pathways in a metabolic syndrome population.

Thus, the purpose of this study sought to determine the effect of anthocyanin supplements on cellular oxidative defenses gene pathways via the expression of Nrf2 dependent gene, lipid, and glucose metabolism by PPRA-γ activation, and NF-KB pathways by reducing inflammation in the mRNA levels. This study is part of a larger clinical trial which will be reported at a larger stage.