Acanthopanax senticosus Rupr Maxim Harms
Acanthopanax senticosus (Rupr. & Maxim.) Harms, a nontoxic herb belongs to the family of Araliaceae, which found in Northeast Asia. A. senticosus traditionally used as a tonic to treat rheumatism, diabetes, and hepatitis . Previous phytochemical and biological investigations found its roots and stem barks include diterpenoids, triterpenoids, lignans, polyacetylenes, phenylpropanoids, flavonoids  and diphenyl ethers . During our efforts on identifying new DGAT1 inhibitors from nature resource, a MeOH extract of the stem of A. senticosus exhibited DGAT inhibitory activity which led us to investigate this plant. In this study, we isolated four new sesqui-lignans along with three known compounds (Fig. 1), and tested their DGAT inhibitory activity.
Conflict of interest
Acknowledgments This research was supported by a grant from KRIBB Research Initiative Program and Technological Developing Scheme of Jilin Province of People's Republic of China (20150101225JC), and (2013G020).
Plasma concentrations of triglycerides, very low-density lipoprotein (VLDL), and intermediate-density lipoprotein (IDL) are increased, and triglyceride content of various lipoproteins is elevated in humans and animals with nephrotic syndrome, , , , , . This is accompanied by impaired clearance of VLDL, chylomicrons, and their remnants in nephrotic syndrome, , , , , , . The latter is caused by down-regulations of lipoprotein lipase, hepatic triglyceride lipase, and VLDL receptor, which are the primary pathways of plasma triglyceride-rich lipoprotein clearance. These findings point to the role of impaired catabolism of triglyceride-rich lipoproteins in the pathogenesis of hypertriglyceridemia in nephrotic syndrome. In addition, increased hepatic production of fatty acids and triglycerides has been demonstrated in various models of nephrotic syndrome, , , . Increased hepatic production of fatty acids in rats with nephrotic syndrome has been shown to be caused by elevated enzymatic activity of acyl-CoA carboxylase and fatty tnf alpha inhibitor synthase, the key enzymes in fatty acid biosynthesis. However, because of the lack of appropriate molecular tools, the precise mechanism of increased hepatic triglyceride synthesis in nephrotic syndrome has not been investigated. Acyl CoA: diacylglycerol acyltransferase (DGAT) is an endoplasmic reticulum membrane–associated enzyme that catalyzes the final step in biosynthesis of triglycerides by covalently joining a long chain fatty acylCoA to diacylglycerol. DGAT plays a critical role in a number of major physiologic functions, such as intestinal lipid absorption, packaging of lipoproteins, storage of fat in adipose tissue and muscle, milk and egg production, which all depend on triglyceride synthesis. Although existence of DGAT activity has been known for many years, and the enzyme had been partially purified, until recently the genes encoding DGAT were not identified. Cases were the first to identify the mouse cDNA for a DGAT that was subsequently termed DGAT-1. Cells infected with the virus harboring DGAT-1 gene were shown to produce a 498 amino acid, 47-kD protein with exclusive substrate specificity for diacylglycerol and acyl-CoA. The enzyme is expressed in all human and mouse tissues. Although DGAT-1 is most abundant in the small intestine, it is not entirely essential for intestinal absorption of triglycerides or production of chylomicrons because these processes are not severely impaired in DGAT-1–deficient mice. DGAT-1 is a member of the ACAT-DGAT gene family. It has 20% sequence homology with ACAT, which uses sterol as opposed to diglycerol as the acyl acceptor. Interestingly, while exhibiting reduced body fat, resistance to diet-induced obesity and lactation defect, DGAT-1 knockout mice have normal plasma triglycerides concentration and abundant adipocyte triglyceride content. These observations led to identification of DGAT-2, which bears no sequence homology with DGAT-1 and, unlike the latter, its activity is inhibitable by high concentration (100 mmol/L) of MgCl. DGAT-2 is abundantly expressed in the liver and white fat, but unlike DGAT-1, is minimally expressed in the small intestine. Based on its cDNA sequence, DGAT-2 is expected to encode a 388 amino acid protein with an approximate molecular mass of 44.5 kD. Relative preservation of intestinal absorption in DGAT-1 knockout mice is, in part, caused by a compensatory up-regulation of DGAT-2 and diglycerol acyltransferase.