Cichoric Acid Prevents Free-Fatty-Acid-Induced Lipid Metabolism Disorders via Regulating Bmal1 in HepG2 Cells

Abstract

Cichoric acid (CA), a polyphenol component from Echinacea purpurea, exhibits preventive effects on liver lipid-metabolism disorders in obesity. This research aimed to determine the role of circadian rhythm signaling during the process of CA-attenuated lipid accumulation in hepatocytes. In the current study, CA treatments improved cell morphology changes and hepatic lipid levels, which were triggered by free fatty acids (2:1, oleate: palmitate) in a dose-dependent way. Besides, CA (200 μM) regulated the circadian rhythm expressions of clock genes and the relatively shallow daily oscillations. Moreover, silencing Bmal1 significantly blocked the p-Akt/Akt pathway to 80.1% ± 1.5% and the p-GSK3β/GSK3β pathway to 64.7% ± 2.8% ( p < 0.05). Furthermore, silencing Bmal1 elevated the expressions of FAS and ACC to 122.4% ± 5.6% and 114.9% ± 1.7% in protein levels ( p < 0.05) and to 166.5% ± 18.5% and 131.4% ± 5.5% in mRNA levels ( p < 0.05). Therefore, our results demonstrated that CA has a Bmal1 resistance to lipid accumulation by enhancing the Akt/GSK3β signaling pathways and modulating the downstream expressions related to lipid metabolism, which indicated that CA might be useful as a natural and promising nonalcoholic fatty liver diseases (NAFLD) modulator.

Resveratrol Maintains Lipid Metabolism Homeostasis via One of the Mechanisms Associated with the Key Circadian Regulator Bmal1

“…Epidemiological studies have shown that circadian misalignment is associated with a range of diseases, such as obesity, NAFLD, and IR [34,35]. Oleic acid (OA) (C18:1) and palmitic acid (PA) (C16:0), two of the most abundant fatty acids in the human diet, could significantly disrupt the circadian rhythm and damage biological clock function [21,22,36]. Consistent with the previous study, we found that the control group maintained a relatively good oscillation rhythm, whereas FFA addition down-regulated the expression of Clock, Bmal1, and Clock-related genes and engendered peak ectopic (Figure 5).…”

“…Malhi et al found that OA (C18:1) and PA (C16:1) are lipotoxic to primary hepatocytes, HepG2 cells, Huh7 cells (a human hepatoma cell line), and MRH7777 cells (a rat hepatocellular carcinoma cell line) and induce apoptosis in adipocytes [44]. Concurrently, FFA (OA:PA = 2:1) treatment induces lipid metabolism disorders, and the increased influx of FFAs into the liver is one of the key pathogenic processes [21,45]. Similarly, in this study, FFA treatment led to intracellular lipid droplet accumulation and upregulated the expression of lipid synthesis-related proteins, as well as insulin signaling pathway dysfunction (Figure 1D, Figure 2A, and Figure S1E).…”

“…Similarly, in this study, FFA treatment led to intracellular lipid droplet accumulation and upregulated the expression of lipid synthesis-related proteins, as well as insulin signaling pathway dysfunction (Figure 1D, Figure 2A, and Figure S1E). A large number of functional food factors are involved in lipid metabolism regulation, such as nobiletin, sesamol, and cichoric acid [21]. NobiletinNOB effectively reversed glucolipid metabolism disorders triggered by PA by increasing the insulin/IGF-1 signaling pathway and regulating key enzymes of de novo lipogenesis [22].…”

“…A high-fat diet (HFD) in mice leads to an altered locomotor activity rhythm and changes in the expression and cycling of core circadian clock genes, as well as nuclear receptors that regulate clock transcription factors in the liver [20]. Additionally, we have recently reported that FFA or palmitic acid (PA) treatment in mouse primary hepatocytes and HepG2 cells markedly weaken mRNA and protein expression levels of Clock and Bmal1 [21,22]. Many regulators and enzymes of lipid biosynthesis and catabolism are dominated via the circadian gene network [13].…”

“…Bioactive components in natural foods, such as proanthocyanidins, (-)-Epigallocatechin-3-gallate (EGCG), chicoric acid, and nobiletin, can manipulate circadian rhythms to ameliorate metabolic syndrome [21,22,23]. Resveratrol (RES, 3,5,4′-trihydroxystilbene), a natural product derived from grapes, has various health benefits, including anti-inflammatory, anti-oxidant, and anti-mutation properties [24].…”