Piperine Improves Lipid Dysregulation by Modulating Circadian Genes Bmal1 and Clock in HepG2 Cells

Abstract

Metabolic disorders are closely associated with the dysregulation of circadian rhythms. Many bioactive components with lipid metabolism-regulating effects have been reported to function through circadian clock-related mechanisms. As the main pungent principle of black pepper, piperine (PIP) has been demonstrated to possess anti-obesity bioactivity by affecting hepatic lipid metabolism-related factors. However, whether the circadian clock genes Bmal1 and Clock are involved in the protective effect of PIP against lipid metabolism disorders remains unknown. In this work, oleic acid (OA) induced lipid accumulation in HepG2 cells. The effect of PIP on redox status, mitochondrial functions, and circadian rhythms of core clock genes were evaluated. Results revealed that PIP alleviated circadian desynchrony, ROS overproduction, and mitochondrial dysfunction. A mechanism study showed that PIP could activate the SREBP-1c/PPARγ and AMPK/AKT-mTOR signaling pathways in a Bmal1/Clock-dependent manner in HepG2 cells. These results indicated that Bmal1 and Clock played important roles in the regulating effect of PIP on hepatic lipid homeostasis.

The Interconnection between Hepatic Insulin Resistance and Metabolic Dysfunction-Associated Steatotic Liver Disease—The Transition from an Adipocentric to Liver-Centric Approach

“…Further and deeper research needs to be performed in order to find new approaches for ameliorating metabolic disorders by targeting biological clock and circadian synchronization. Recent research conducted in vitro on cultured hepatocytes showed that BMAL1 and CLOCK play an important role in the regulation of hepatic lipid homeostasis by modulating the SREBP1c/PPARγ signaling pathway [26], confirming the significant role of circadian rhythm in MASLD development and progression [27][28][29].…”

Berberine Ameliorates Metabolic-Associated Fatty Liver Disease Mediated Metabolism Disorder and Redox Homeostasis by Upregulating Clock Genes: Clock and Bmal1 Expressions

“…It has been observed that abnormalities in circadian rhythm genes are directly connected with metabolic disruption [ 32 , 33 ]. The protein-to-protein interaction network for Clock, Bmal1 (ARNTL), and other circadian rhythm genes from STRING protein database ( , accessed on 6 September 2022) is shown in Figure 3 F. The hepatic expression Clock and Bmal1 proteins by Western blot were remarkably decreased in the MAFLD group, which can be significantly increased with the BBR treatment ( p < 0.05) in Figure 2 I,J.…”

The gut-liver axis in fatty liver disease: role played by natural products

“…Piperine (PIP) found in large quantities in Piper nigrum L. that has anti-obesity, anti-inflammatory, and hepatoprotective properties ( Cheng et al, 2023 ; Joshi et al, 2023 ). In vitro studies have found that PIP regulates lipid metabolism in HepG2 cells in a Bmal1/Clock-dependent manner ( Zhang et al, 2022 ) and in vivo studies have found that PIP ameliorates insulin resistance in diabetic mice constructed by subcutaneous injection of monosodium glutamate (MSG) in neonatal mice ( Liu et al, 2020 ). Piperine was administered at 20 and 40 mg/kg body weight per day in an obese mouse model induced by high-fat dietary feeding.…”