It has been shown that insulin resistance is associated with increased hepatic lipid and causes hepatic steatosis through a myriad of mechanisms, including inflammatory signaling. Methods Helminthostachys zeylanica HZ is used widely as a common herbal medicine to relieve fever symptoms and inflammatory diseases in Asia. After 12 weeks of a high-fat diet with HZ extract treatment, the HFD mice were protected from hyperlipidemia and hyperglycemia. HZ extract prevented body weight gain, adipose tissue expansion and adipocyte hypertrophy in the HFD mice.
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It has been shown that insulin resistance is associated with increased hepatic lipid and causes hepatic steatosis through a myriad of mechanisms, including inflammatory signaling. Methods Helminthostachys zeylanica HZ is used widely as a common herbal medicine to relieve fever symptoms and inflammatory diseases in Asia. After 12 weeks of a high-fat diet with HZ extract treatment, the HFD mice were protected from hyperlipidemia and hyperglycemia.
HZ extract prevented body weight gain, adipose tissue expansion and adipocyte hypertrophy in the HFD mice. In addition, fat accumulation was reduced in mice livers. Moreover, the insulin sensitivity-associated index, which evaluates insulin function, was also significantly restored.
Conclusions These results suggest that HZ has a promising pharmacological effect on high-fat diet-induced obesity, hepatic steatosis and insulin resistance, which may have the potential for clinical application. Peer Review reports Background Obesity, fatty liver and dysregulated insulin action are strongly associated and are currently a worldwide health problem [ 1 ].
Fatty liver is the initial stage of nonalcoholic fatty liver disease NAFLD , which is caused by an imbalance of lipid metabolism and is a common metabolic symptom [ 2 ]. NAFLD and type 2 diabetes mellitus T2DM frequently coexist because of sharing the similar pathogenic features of excess adiposity and insulin resistance [ 3 ].
Although the mechanisms involved in lipid-induced insulin resistance are not fully understood, it is well-known that nonalcoholic fatty liver disease NAFLD , which causes nonalcoholic steatohepatitis NASH , is one of the most relevant factors that leads to metabolic diseases and insulin resistance [ 5 ].
Indeed, therapies for fatty liver disease are aimed at reducing body weight and improving insulin sensitivity to alleviate the associated metabolic syndrome [ 6 , 7 ]. Now, novel therapeutic strategies for NAFLD progression have stimulated great interest in terms of developing effective treatments for lipid-associated metabolic disorders [ 8 ]. Helminthostachys zeylanica L.
HZ , the only fern-like plant of the Ophioglossaceae, is distributed widely in Southeast Asia and has been used as a folk medicine for centuries [ 9 ]. It has been shown that HZ contains prenylated flavonoids and quercetin, which have inhibitory effects on human neutrophils [ 10 ]. In addition, the main components in HZ, flavonoids, have antioxidant and anti-inflammatory activities [ 10 , 11 ]. Previous studies have shown that one of the main compounds in HZ, ugonin K, promotes osteogenesis through the Src-associated pathway and activates downstream Runx2 and oxterix [ 12 ].
Furthermore, HZ extract was considered to have neuroprotective activity because of its anti-inflammatory activity on human astrocytes, through bradykinin-induced MMP-9 signaling [ 13 ]. Another bioactive compound extracted from HZ, ugonin J, is considered to be a potential inhibitor of cell migration and neointima formation through MMP-2 and -9 pathways [ 14 ]. Rhizomes of HZ have been used for variety of purposes, including protection against liver damage [ 15 ]. However, the therapeutic effect of HZ on abnormalities of lipid and glucose metabolism remains unclear.
Because of the vicious circle between NAFLD and insulin resistance, in this study, we applied our optimized human fatty liver cell model and HFD mouse model of metabolic disorder and investigated the potential restorative therapeutic effects of HZ.
Methods H. HZ rhizomes g were heated and extracted with 2. The filtrate was concentrated and lyophilized to yield HZ extract 29 g, yield 5. Purification of ugonin J and ugonin K The preparation of ugonins J and ugonin K were prepared as described previously [ 11 ]. The filtrate volume was then adjusted to 50 ml with the same solvent. Louis, MO. Western blot analysis was performed as described previously [ 16 ]. Shimotohno Kyoto University, Japan and maintained as described previously [ 18 ].
DMSO was used as the vehicle for experimental control. The liver and adipose tissue were removed, rinsed with physiological saline, weighed, immediately frozen in liquid nitrogen, and stored until analysis. Biochemical characterization of plasma and histological analysis of fat and liver tissues The plasma, epididymis adipose, and liver tissues were collected from each sacrificed mouse.
The biochemical analysis of plasma and histological analysis of the fat and liver tissues were performed as described previously [ 20 ]. Results Identification of major components in H. HPLC analysis was performed on the HZ extract and two of the individual ingredients, ugonins J and K were isolated [ 11 ] and used as standard markers for quality control of HZ material.
Two major peaks were identified in the HZ extract. The chemical structures of the ugonins are shown Full size image The effect of HZ on palmitate-induced cellular lipid accumulation in a human fatty liver cell model Fatty liver disease is mainly attributable to triglyceride accumulation in the hepatocytes [ 21 ].
The lipid content of the cells was observed by Oil-Red O staining and quantified. As shown in Fig. Because we found HZ extract had an inhibitory effect on lipid deposition in human hepatocytes, possible molecular mechanisms were explored. AMP-activated protein kinase AMPK was reported to regulate fat metabolism in the liver and change with cellular energy status [ 22 ].
Ugonins J and K are structurally related to natural flavonoid luteolin [ 23 ], which has been demonstrated to attenuate hepatic steatosis [ 24 ]. Therefore, the agent luteolin was used as a positive control drug in the subsequent experiment. HZ extract significantly increased ACC protein phosphorylation. Tubulin served as a loading control. Quantitative analysis with Multi Gauge V3.
ND vs. Compared to the palmitate group, HZ extract substantially decreased sterol regulatory element-binding transcription factor 1c SREBP-1c protein expression, which is involved in fatty acid synthesis Fig. Treatment with HZ extract greatly increased CPT1 protein expression, compared to the palmitate group.
We determined whether lipid metabolism-related genes in the hepatocytes were influenced by HZ intervention. This suggests that HZ extract causes reduced food uptake, which may be the reason the mice gain less weight. HFD vs. Therefore, the epididymis adipose tissue EAT was dissected and measured after 12 weeks of experimental diet. It is suggested that the presence of hypertriglyceridemia and the high cholesterol phenomenon in the HFD mouse model is consistent with the symptom of obesity in humans, which suggests the HZ extract has the potential to inhibit hyperlipidemia bioactivity.
To examine the effect of HZ on fatty liver, the liver was weighed and markers of hepatic-steatosis were evaluated to determine the incidence of steatohepatitis. The increasing weight of the liver may be attributable to lipid accumulation.
Helminthostachys zeylanica (L.) Hook.