Abstract
The activation of nuclear factor erythroid 2-related factor 2 (Nrf2) is closely related to the alleviation of nonalcoholic fatty liver disease (NAFLD) by regulating oxidative stress and lipid homeostasis. Gentiopicroside (GPS), an iridoid glycoside found in the Gentianaceae, possesses anti-inflammatory and antioxidant effects. However, the protective effects of GPS on lipid accumulation and oxidative damage have not been investigated thoroughly in free fatty acid- (FFA-) induced HepG2 cells and tyloxapol- (Ty-) induced hyperlipidemia mice. Cell counting kit-8 assays, Oil Red O staining, Western blotting analysis, extraction of nuclear and cytosolic proteins, and biochemical index assay were employed to explore the mechanisms by which GPS exerts a protective effect on FFA-induced HepG2 cells and Ty-induced hyperlipidemia mouse model. This paper demonstrates that GPS could effectively alleviate NAFLD by elevating cell viability, reducing fatty deposition, downregulating TG, and activating nucleus Nrf2 in FFA-induced HepG2 cells. Meanwhile, GPS significantly regulated the activation of phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway, Nrf2 antioxidant pathway, peroxisome proliferator-activated receptor α (PPARα), and GPS-inhibited sterol regulatory element-binding protein-1c (SREBP-1c) expression in FFA-stimulated lipid accumulation of HepG2 cells and Ty-treated mice. Interestingly, we highlight that PI3K/AKT inhibitor (LY294002) markedly increased the expression of Nrf2 antioxidant pathway, PPARα, and downregulated SREBP-1c in FFA-stimulated HepG2 cells. For these reasons, we found that the deletion of Nrf2 could lose the protective effects of GPS on the Nrf2 antioxidant pathway and PPARα activation and SREBP-1c inactivation in FFA-stimulated HepG2 cells and Ty-treated mice. GPS treatment had no effect on abnormal lipogenesis and antioxidant enzymes in Ty-induced Nrf2−/− mice. This work gives a new explanation that GPS may be a useful therapeutic strategy for NAFLD through upregulation of the Nrf2 antioxidant pathway, which can alleviate oxidative damage and lipid accumulation.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is a multisystem disease that is the commonest cause of chronic liver metabolic disease in Western countries
Deletion of nuclear factor erythroid 2-related factor 2 (Nrf2) upregulated SREBP-1c and HO-1 expression in GPS treatment cells (Figures 5(a), 5(c), and 5(g)). These results suggested that deletion of Nrf2 extremely significantly blunted GPS treatment antioxidative stress and antilipogenesis effects, of which the assumption was that Nrf2 activation plays an important role in GPS-treated and free fatty acid- (FFA-)stimulated HepG2 cells
Our results demonstrated that GPS treatment markedly elevated AKT phosphorylation and increased protein levels of Nrf2, HO-1, NQO1, and GCLM in Ty-induced oxidative stress mice (Figures 7(a)–7(f))
Summary
Nonalcoholic fatty liver disease (NAFLD) is a multisystem disease that is the commonest cause of chronic liver metabolic disease in Western countries. The “one-hit,” “two-hit,” and “multiple-hit” hypotheses have been used to explain the pathogenesis of NAFLD. The “multiple-hit” hypothesis provides more precise explanations of NAFLD pathogenesis [2]. The “multiple-hit” hypothesis comprises (1) the insulin resistance, lipotoxicity, and disorder of fat metabolism caused by mitochondrial dysfunction, endoplasmic reticulum stress, and inflammasome activation; (2) the dysfunction of adipose tissue; (3) the genetic determinants; (4) the epigenetic factors; and (5) the dietary factors [2]. Simple accumulation of lipid plays a Oxidative Medicine and Cellular Longevity key role in the development of NAFLD [3]. Abnormal lipid metabolism can produce lipotoxicity that induces oxidative stress [4]. The present study will focus on the inhibition of the accumulation of lipid and oxidative damage
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