BackgroundOligonol is a low molecular weight form of polyphenol polymers derived from lychee fruits. Several studies suggest that Oligonol has an anti-obesity effect. Since obesity is tightly associated with insulin resistance, we investigated a possible remission effect of Oligonol on lipid accumulation and insulin resistance in human hepatic HepG2 cells.MethodsHepG2 cells were treated with palmitate for 24 h to induce cellular hepatic steatosis and insulin resistance. The cells were then treated with Oligonol at subtoxic concentrations and examined for lipid metabolism, cytokine production, and insulin signaling using quantitative RT-PCR and western blot analysis.ResultsOligonol treatment reversed the palmitate-induced intracellular lipid accumulation, down regulated the expression of lipogenic genes, and up-regulated genes for fatty acid degradation. Oligonol restored insulin sensitivity, as was determined by the phosphorylation states of IRS-1. Oligonol also inhibited STAT3-SOCS3 signaling and increased AMPK phosphorylation in HepG2 cells.ConclusionOligonol treatment improved palmitate-induced cellular steatosis and insulin resistance in HepG2 cells with concomitant reduction of inflammatory cytokines and decrease in STAT3-SOCS3 and AMPK-mTOR pathways. Oligonol may have beneficial effects in lipid metabolism and insulin resistance in the liver.

(2015) Chronic HMGCR/HMG-CoA reductase inhibitor treatment contributes to dysglycemia by upregulating hepatic gluconeogenesis through autophagy induction, Autophagy, 11:11, 2089-2101, DOI: 10.1080/15548627.2015 Keywords: autophagy, diabetes, gluconeogenesis, HMG-CoA reductase inhibitor, statin Abbreviations: ACTB, actin beta; AKT1, v-akt murine thymoma viral oncogene homolog 1; ATG7, autophagy-related 7; Baf A1, bafilomycin A 1 ; BECN1, Beclin 1 autophagy related; CQ, chloroquine; FOXO1, forkhead box O1; G6PC, glucose-6-phosphatase catalytic subunit; GCK, glucokinase (hexokinase 4); GFP, green fluorescent protein; HMGCR/HMG-CoA reductase, 3-hydroxy-3-methylglutaryl-CoA reductase; MAP1LC3A/LC3A, microtubule-associated protein 1 light chain 3 alpha; MTOR, mechanistic target of rapamycin (serine/threonine kinase); O-GluNAc, O-linked b-N-acetyl glucosamine; PCK1, phosphoenolpyruvate carboxykinase 1 (soluble); PIK3C3, phosphatidylinositol 3-kinase catalytic subunit type 3; PKLR, pyruvate kinase liver and RBC; qRT-PCR, quantitative reverse transcription-polymerase chain reaction; RFP, red fluorescent protein; RPS6KB1, ribosomal protein S6 kinase; 70kDa, polypeptide 1; shRNA, short hairpin RNA; T2DM, type 2 diabetes mellitus; XBP1, X-box binding protein 1.Statins (HMGCR/HMG-CoA reductase [3-hydroxy-3-methylglutaryl-CoA reductase] inhibitors) are widely used to lower blood cholesterol levels but have been shown to increase the risk of type 2 diabetes mellitus. However, the molecular mechanism underlying diabetogenic effects remains to be elucidated. Here we show that statins significantly increase the expression of key gluconeogenic enzymes (such as G6PC [glucose-6-phosphatase] and PCK1 (phosphoenolpyruvate carboxykinase 1 [soluble]) in vitro and in vivo and promote hepatic glucose output. Statin treatment activates autophagic flux in HepG2 cells. Acute suppression of autophagy with lysosome inhibitors in statin treated HepG2 cells reduced gluconeogenic enzymes expression and glucose output. Importantly, the ability of statins to increase gluconeogenesis was impaired when ATG7 was deficient and BECN1 was absent, suggesting that autophagy plays a critical role in the diabetogenic effects of statins. Moreover autophagic vacuoles and gluconeogenic genes expression in the liver of diet-induced obese mice were increased by statins, ultimately leading to elevated hepatic glucose production, hyperglycemia, and insulin resistance. Together, these data demonstrate that chronic statin therapy results in insulin resistance through the activation of hepatic gluconeogenesis, which is tightly coupled to hepatic autophagy. These data further contribute to a better understanding of the diabetogenic effects of stains in the context of insulin resistance.

Polyphenols have recently become an important focus of study in obesity research. Oligonol is an oligomerized polyphenol, typically comprised of catechin-type polyphenols from a variety of fruits, which has been found to exhibit better bioavailability and bioreactivity than natural polyphenol compounds. Here, we demonstrated that Oligonol inhibits 3T3-L1 adipocyte differentiation by reducing adipogenic gene expression. During adipogenesis, Oligonol downregulated the mRNA levels of peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer binding proteins α (C/EBPα), and δ (C/EBPδ) in a dose-dependent manner and the expression of genes involved in lipid biosynthesis. The antiadipogenic effect of Oligonol appears to originate from its ability to inhibit the Akt and mammalian target of rapamycin (mTOR) signaling pathway by diminishing the phosphorylation of ribosomal protein S6 kinase (p70S6K), a downstream target of mTOR and forkhead box protein O1 (Foxo1). These results suggest that Oligonol may be a potent regulator of obesity by repressing major adipogenic genes through inhibition of the Akt signaling pathway, which induces the inhibition of lipid accumulation, ultimately inhibiting adipogenesis.

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