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. 2019 Apr 17;8(4):359.
doi: 10.3390/cells8040359.

Therapeutic Application of Micellar Solubilized Xanthohumol in a Western-Type Diet-Induced Mouse Model of Obesity, Diabetes and Non-Alcoholic Fatty Liver Disease

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Free PMC article

Therapeutic Application of Micellar Solubilized Xanthohumol in a Western-Type Diet-Induced Mouse Model of Obesity, Diabetes and Non-Alcoholic Fatty Liver Disease

Abdo Mahli et al. Cells. .
Free PMC article

Abstract

Xanthohumol (XN), a prenylated chalcone from hops, has been reported to exhibit a variety of health-beneficial effects. However, poor bioavailability may limit its application in the prevention and therapy of diseases. The objective of this study was to determine whether a micellar solubilization of xanthohumol could enhance the bioavailability and biological efficacy of xanthohumol in a Western-type diet (WTD) induced model of obesity, diabetes and non-alcoholic fatty liver disease (NAFLD). After 3 weeks feeding with WTD, XN was additionally applied per oral gavage as micellar solubilizate (s-XN) or native extract (n-XN) at a daily dose of 2.5 mg/kg body weight for a further 8 weeks. Control mice received vehicle only in addition to the WTD. WTD-induced body weight-gain and glucose intolerance were significantly inhibited by s-XN application. Furthermore, WTD-induced hepatic steatosis, pro-inflammatory gene expression (MCP-1 and CXCL1) and immune cell infiltration as well as activation of hepatic stellate cells (HSC) and expression of collagen alpha I were significantly reduced in the livers of s-XN-treated mice compared to WTD controls. In contrast, application of n-XN had no or only slight effects on the WTD-induced pathological effects. In line with this, plasma XN concentration ranged between 100-330 nmol/L in the s-XN group while XN was not detectable in the serum samples of n-XN-treated mice. In conclusion, micellar solubilization enhanced the bioavailability and beneficial effects of xanthohumol on different components of the metabolic syndrome including all pathological steps of NAFLD. Notably, this was achieved in a dose more than 10-fold lower than effective beneficial doses of native xanthohumol reported in previous in vivo studies.

Keywords: diabetes; micellar solubilisation; non-alcoholic fatty liver disease; obesity; xanthohumol.

Conflict of interest statement

The authors declare no conflict of interest. C.H. and J.F. are consultants of AQUANOVA AG, and AM, TS and KF are working in the laboratory of C.H. All authors had complete and independent control over the study design, analysis and interpretation of data, report writing, and publication, regardless of results.

Figures

Figure 1
Figure 1
Effects of solubilized xanthohumol on body weight gain and serum glucose levels in mice fed with a Western-type diet (WTD). Mice were fed either with control diet or a Western-type diet (WTD) for three weeks. Subsequently, WTD-fed mice were treated with either n-XN or s-XN or vehicle (VH) per oral gavage daily for additional 8 weeks. (a) Body weight during the experiment. Arrow indicates start of treatment. (b) Body weight 11 weeks after start of WTD feeding (i.e., 8 weeks after the beginning of the s-XN or n-XN application). (c) Representative pictures of mice after 11 weeks of control or WTD-feeding. (d) Laparotomy showing massively increased visceral and subcutaneous white adipose tissue depots of WTD compared with the Ctr. or XN-treated groups. (e) Fasting Glucose levels. (f) Glucose levels derived from a glucose tolerance test over the time (left panel) and after 120 min (right panel). (*: p < 0.05 in comparison with vehicle (VH); #: p < 0.05 in comparison with Ctr.).
Figure 2
Figure 2
Effect of solubilized xanthohumol on hepatic steatosis in mice fed with a Western-type diet. Mice were fed either with control diet or a Western-type diet (WTD) for three weeks. Subsequently, WTD-fed mice were treated with either n-XN or s-XN or vehicle (VH) per oral gavage daily for additional 8 weeks. (a) Macroscopic images (upper pictures) and histological staining (hematoxylin/eosin; lower pictures) of the livers. (b) Liver to body weight ratio. (c) Hepatic triglyceride (TG) content normalized to total hepatic protein. (*: p < 0.05 in comparison with vehicle (VH); #: p < 0.05 in comparison with Ctr.).
Figure 3
Figure 3
Effect of solubilized xanthohumol on hepatic inflammation in mice fed with a Western-type diet. Mice were fed either with control diet or a Western-type diet (WTD) for three weeks. Subsequently, WTD-fed mice were treated with either n-XN or s-XN or vehicle (VH) per oral gavage daily for additional 8 weeks. mRNA levels of (a) MCP1 (CCL2) and (b) CXCL1 analyzed by quantitative RT-PCR. (c) Microscopic images of CD3 immunohistochemical staining of liver tissue (left panel) and quantification of CD3-stained cells (right panel) (*: p < 0.05 in comparison with vehicle (VH); #: p < 0.05 in comparison with Ctr.).
Figure 4
Figure 4
Effect of solubilized xanthohumol on hepatic fibrosis in mice fed with a Western-type diet. Mice were fed either with control diet or a Western-type diet (WTD) for three weeks. Subsequently, WTD-fed mice were treated with either n-XN or s-XN or vehicle (VH) per oral gavage daily for an additional 8 weeks. (a) Hepatic mRNA levels of α-SMA analyzed by quantitative RT-PCR. (b) Microscopic images of α-SMA immunohistochemical staining of liver tissue. (c) Hepatic COL1A1 mRNA analyzed by quantitative RT-PCR (*: p < 0.05 in comparison with vehicle (VH); #: p < 0.05 in comparison with Ctr.).

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