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Received Sep 29, 2017; Revised Dec 22, 2017; Accepted Jan 11, 2018
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1. Introduction
The liver plays a key role in lipid metabolism. It is well known that a high‐carbohydrate diet can prime the hepatic de novo lipogenesis (DNL) pathway with a large substrate load and, thus, increase the rate of DNL [1]. Accumulation of lipid droplets in the hepatocytes has been closely related to obesity, insulin resistance, type 2 diabetes, and nonalcoholic fatty liver diseases (NAFLD) [2, 3]. Elevated hepatic DNL was observed in insulin resistance condition [4–6]; therefore, a finding of high DNL rate in an individual may provide early warning of the possible development of type 2 diabetes mellitus. Therefore, the prevention of increased DNL in the liver may provide a therapeutic strategy for the management of multiple stages of NAFLD.
Hepatic AMP-activated protein kinase (AMPK) is thought to play a pivotal role in regulating lipid metabolism, glucose homeostasis, and insulin sensitivity [7, 8]. As an energy sensor maintaining cellular glucose homeostasis, AMPK significantly inhibits hepatic glucose output by transcriptional control [9]. In addition, AMPK regulates acyl coenzyme A (acyl-CoA) channeling towards β-oxidation and away from glycerolipid biosynthesis. AMPK phosphorylates and downregulates acetyl-CoA carboxylase (ACC), thereby decreasing the production of malonyl-CoA. Sterol regulatory element-binding proteins (SREBPs) are key lipogenic transcription factors that regulate the expression of lipogenic enzymes, including ACC, fatty acid synthase (FAS), and 3-hydroxy-3-methylglutaryl-CoA reductase [10–12]. Overexpression of hepatic SREBP-1c results in selective induction of lipogenic gene expression, with no effect on the genes involved in cholesterol synthesis [13]. Moreover, the phosphorylation of AMPK inactivates SREBP-1 and inhibits hepatic lipid accumulation in a high-fat diet-induced mouse [14, 15].
Nobiletin, a major component in citrus fruits [16], has been used in traditional Chinese herbal medicine [17]. It has been shown to possess several biological activities, including anti-inflammatory [18], antitumor [19], antidiabetic [20], and antiobesity [21] effects, as well as play an important role in the prevention of postprandial hyperglycemia [22] and hyperlipidemia [23]. However, the molecular mechanisms underlying its effects on hepatic lipid metabolism, particularly with regard to the activation...