Lithospermum erythrorhizon Root and its Naphthoquinones Repress SREBP1c and Activate PGC1α Through AMPKα

Abstract

Objective: To examine specific molecular mechanisms involved in modulating hepatic lipogenesis and mitochondria biogenesis signals by Lithospermum erythrorhizon (gromwell) root extract. Methods: Stable cell lines with luciferase reporter constructs were generated to examine sterol regulatory element binding protein 1c (SREBP1c) and peroxisome proliferator-activated receptor gamma, coactivator 1 (PGC1) a promoter activity and estrogen-related receptor (ERR) a response element activity. Gene expression of SREBP1c, stearoyl coenzyme A desaturase 1, and PGC1a was measured by using reverse transcription polymerase chain reaction. Lipogenesis was measured in human hepatoma cells with Nile red staining and flow cytometry. Phosphorylation of AMP-activated protein kinase (AMPK) a was determined by using ELISA and Western blot. Results: Gromwell root extract and its naphthoquinones dose-dependently repressed high glucose and liver X receptor a induction of SREBP1c promoter activity and gene expression. Hepatic lipogenesis was repressed, and PGC1a promoter and gene expression and ERRa response element activity were increased by gromwell root extract. Gromwell root extract, shikonin, and a-methyl-n-butyrylshikonin increased AMPKa phosphorylation, and inhibition of AMPK blunted the repression in SREBP1c promoter activity by gromwell root extract and its naphthoquinones. Conclusions: Data suggest that gromwell root extract and its naphthoquinones repress lipogenesis by increasing the phosphorylated state of AMPKa and stimulating mitochondrial biogenesis signals.

Protective Effect of a Mixture of Astragalus membranaceus and Lithospermum erythrorhizon Extract against Hepatic Steatosis in High Fat Diet‐Induced Nonalcoholic Fatty Liver Disease Mice

“…A previous study by Duan [24] reported that calycosin, a major component of Astragali radix, ameliorates HFD-induced NAFLD by inhibiting gluconeogenesis through the modulation of Farnesoid X receptor (FXR) activation. In addition, shikonin, which is one of the naphthoquinones in LE, suppresses lipogenesis by increasing the phosphorylated AMPK in hepatocytes [30]. Based on these findings, we postulated that ALM16 would possess a certain level of cartilage protective effect and could exert multiple biological activities under various pathological conditions.…”

“…LE contains naphthoquinones, including shikonin and its derivatives, identified as the major phytochemicals [27]. Recent studies have reported the various biological activities of LE, including anti-inflammatory, antiobesity, and antilipogenic activities [28][29][30]. Especially, Gwon et al reported that ethanol extract of LE, which contains acetylshikonin as the main compound, exerted antiobesity effect through inhibition of lipogenic and adipogenic gene expression [29].…”

Hydroxytyrosol Plays Antiatherosclerotic Effects through Regulating Lipid Metabolism via Inhibiting the p38 Signal Pathway

“…Moreover, AMPK, a phylogenetically conserved serine/threonine protein kinase, is an energy sensor that controls intracellular energy metabolism [ 36 ]. Once activated, AMPK is capable of inducing a series of biological activities for regulating the lipid metabolism, including the suppression of SREBP2 activation and upregulation of PGC-1 α [ 37 ]. In this study, the Western blot analysis indicated that HT administration obviously increased the activation of AMPK, suggesting that HT might activate AMPK to block the signal transduction of the downstream SREBP2/PCSK9 pathway, consequently resulting in the level reduction of blood LDL-C and alleviation of atherosclerosis development ( Figure 6 ).…”

Non‑cytotoxic doses of shikonin inhibit lipopolysaccharide‑induced TNF‑α expression via activation of the AMP‑activated protein kinase signaling pathway

“…Shikonin, a naphthoquinone compound, is the primary active constituent of Zicao, which can be produced from the dried root of Lithospermum erythrorhizon (34). Shikonin has been reported to exert multiple pharmacological effects, including both anti-cancer and anti-inflammatory properties (35,36). However, the strong non-selective cytotoxicity of shikonin restricts its clinical application (36).…”