Isosilybin regulates lipogenesis and fatty acid oxidation via the AMPK/SREBP-1c/PPARα pathway

Non-alcoholic fatty liver disease (NAFLD) is a growing worldwide epidemic which has become the main cause of chronic liver diseases. The global prevalence of NAFLD is currently estimated to be 25% with a consistent trend in increasing rates [1]. Notably, there are currently more than 240 million NAFLD patients in China, accounting for more than one-fifth of the global NAFLD population [2]. The common pathological features of NAFLD are hepatic steatosis and lipid accumulation without excessive alcohol consumption or other factors of liver injury. Liver is the main site for apolipoprotein synthesis, fatty acid oxidation and ketone body formation. NAFLD-related hepatic steatosis includes dysfunction of lipid synthesis, lipid oxidation and lipid transport in hepatocytes.

AMP-activated protein kinase (AMPK) is a heterotrimer comprised of α, β, and γ subunits. The α subunit contains a catalytic phosphorylation site (Thr172) in the NH2-terminal site that can be phosphorylated by the upstream protein kinases (LKB1, CaMKK, and TAK1) within the catalytic subunit to activate AMPK [3]. The phosphorylated AMPK is an important intracellular energy sensor responsible for regulating insulin sensitivity, glycogen export, fatty acid synthesis, enhancing the utilization and oxidation of fatty acids by mitochondria, and improving hepatic inflammation and fibrosis, so as to reverse NAFLD [4,5]. Increased hepatic lipogenesis of NAFLD patients is attributed to the activation of sterol regulatory element-binding protein 1c (SREBP-1c), a crucial transcription factor that mainly regulates the expression of key adipogenic genes such as fatty acid synthase (Fas) and acetyl-CoA Carboxylase 1 (Acc1), whose activities are under the control of AMPK [6,7]. Activation of AMPK also up-regulates peroxisome proliferator-activated receptor-α (PPARα) and its downstream target genes such as carnitine acyltransferase 1α (Cpt1ɑ), acyl-Coenzyme A oxidase 1 (Acox1), and subsequently promoting fatty acid oxidation and improving the functional integrity of mitochondria [8]. Additionally, active-tion of AMPK signaling pathway ameliorated NAFLD through reducing liver steatosis in diet-induced obese mice and lipid accumulation in oleic acid-induced L02 and HepG2 cells [9,10]. AMPK activator A-769662 (a thienopyridone compound) directly stimulated rat hepatic AMPK and decreased hepatic TG level of ob/ob mice through increasing fatty acid oxidation and inhibiting fatty acid synthesis [11]. The AMPK/SREBP1 pathway plays critical roles in the regulation of fatty acid-induced fatty liver. Stimulation of lipogenesis and lipid accumulation by fatty acid administration is mediated by suppressing the phosphorylation of AMPK and activation of SREBP1 both in vitro and in vivo [12].

Since there are no FDA-approved pharmacological therapies for NAFLD currently, the natural antioxidants found in dietary plants including fruits and vegetables which may have benefit on metabolic disease are considered to be an option to treat NAFLD [13]. Silybum marianum has a long history as a dietary medicinal plant against liver disorders, kidney problems and biliary tract disease, and has been widely used in cooking oil production and dietary supplement in recent years [14,15]. Supplements based on this herb is one of the most commonly used herbal supplement in the United States for liver problems [16]. Silymarin (an extract from seeds and fruits of Silybum marianum) is mainly consisting of four isomers: silibinin A and B, and isosilybin A and B, and has been widely used as an herbal and food supplement to treat disease [17,18]. Silymarin and its components display diverse pharmacological properties in vitro and in vivo such as hepatoprotective, antioxidant, anti-inflammatory and cardioprotective activities [19,20]. Isosilybin has been reported as a potential agonist of PPARγ, suggesting its positive regulation on insulin sensitivity, but whether isosilybin affects insulin signaling pathways in peripheral tissues and lipid metabolism in liver was not reported [21]. Our previous study found that silibinin ameliorated the lipid metabolism and oxidative stress disorder in mice with non-alcoholic steatohepatitis by regulating the CFLAR-JNK pathway [22]. The objective of this study was to investigate the regulation and mechanism of isosilybin on lipid metabolism in hepatocytes with steatosis.

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