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. 2020 Feb 18;12(2):523.
doi: 10.3390/nu12020523.

A Diterpenoid, 14-Deoxy-11, 12-Didehydroandrographolide, in Andrographis p aniculata Reduces Steatohepatitis and Liver Injury in Mice Fed a High-Fat and High-Cholesterol Diet

Yun-Ta Liu  1 , Haw-Wen Chen  1 , Chong-Kuei Lii  1   2 , Jia-Hua Jhuang  1 , Chin-Shiu Huang  2 , Mei-Ling Li  1 , Hsien-Tsung Yao  1
Affiliations

A Diterpenoid, 14-Deoxy-11, 12-Didehydroandrographolide, in Andrographis p aniculata Reduces Steatohepatitis and Liver Injury in Mice Fed a High-Fat and High-Cholesterol Diet

Yun-Ta Liu et al. Nutrients. .

Abstract

14-Deoxy-11,12-didehydroandrographolide (deAND), a diterpenoid in Andrographis paniculata (Burm. f.) Nees, acts as a bioactive phytonutrient that can treat many diseases. To investigate the protective effects of deAND on reducing fatty liver disease, male mice were fed a high-fat and high-cholesterol (HFHC) diet without or with 0.05% and 0.1% deAND supplementation. Cholesterol accumulation, antioxidant, and anti-inflammatory activities in liver and liver injury were evaluated after deAND treatment. The results show that deAND treatment for seven weeks reduced plasma alanine aminotransferase activity and lowered hepatic cholesterol accumulation, tumor nuclear factor-α, and histological lesions. The 0.1% deAND treatment reduced HFHC diet-induced apoptosis by lowering the caspase 3/pro-caspase 3 ratio. After 11 weeks of deAND treatment, increased NOD-like receptor protein 3 (NLRP3), capase-1, and interleukin-1β protein levels in liver were suppressed by deAND treatment. In addition, nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA expression, heme oxygenase-1 protein expression, and the activities of glutathione peroxidase and glutathione reductase were increased in mice fed the HFHC diet. However, those activities of antioxidant enzymes or proteins were also upregulated by 0.1% deAND treatment. Furthermore, deAND treatment tended to lower hepatic lipid peroxides. Finally, deAND treatment reversed the depletion of hepatic glutamate level induced by the HFHC diet. These results indicate that deAND may ameliorate HFHC diet-induced steatohepatitis and liver injury by increasing antioxidant and anti-inflammatory activities.

Keywords: 14-deoxy-11,12-didehydroandrographolide (deAND); Andrographis paniculata; NLRP3 inflammasome; liver injury; steatohepatitis.

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Conflict of interest statement

The authors have no conflicts of interest to report.

Figures

Figure 1
Figure 1
Chemical structure of 14-Deoxy-11,12-didehydroandrographolide (deAND).
Figure 2
Figure 2
Histopathological examination (H&E stain, 400x) of livers in the control group (a), HFHC group (b), HFHC + 0.05% deAND group (c), and HFHC + 0.1% deAND group (d). The small arrow indicates the fat droplets and the large arrow indicates the perivenular inflammatory infiltrates. Normal liver architecture was found in the low-fat control group (a). Figure 2e–h shows histopathological examination of liver fibrosis (masson’s trichrome- stain, 400x) in the control group (e), HFHC group (f), HFHC + 0.05% deAND group (g), and HFHC + 0.1% deAND group (h). The large arrow in HFHC group indicates the collagen (blue color). Hepatic cholesterol and triglyceride contents are shown in (i,j). Values are means ± SD. (n = 5–6). * Significantly different from the Control group, p < 0.05. # Significantly different from the HFHC group, p < 0.05. HFHC, high-fat and high cholesterol. deAND, 14-Deoxy-11,12-didehydroandrographolide.
Figure 2
Figure 2
Histopathological examination (H&E stain, 400x) of livers in the control group (a), HFHC group (b), HFHC + 0.05% deAND group (c), and HFHC + 0.1% deAND group (d). The small arrow indicates the fat droplets and the large arrow indicates the perivenular inflammatory infiltrates. Normal liver architecture was found in the low-fat control group (a). Figure 2e–h shows histopathological examination of liver fibrosis (masson’s trichrome- stain, 400x) in the control group (e), HFHC group (f), HFHC + 0.05% deAND group (g), and HFHC + 0.1% deAND group (h). The large arrow in HFHC group indicates the collagen (blue color). Hepatic cholesterol and triglyceride contents are shown in (i,j). Values are means ± SD. (n = 5–6). * Significantly different from the Control group, p < 0.05. # Significantly different from the HFHC group, p < 0.05. HFHC, high-fat and high cholesterol. deAND, 14-Deoxy-11,12-didehydroandrographolide.
Figure 3
Figure 3
Western blotting analysis of apoptosis index (Caspase 3/pro-caspase 3) in liver (a). The data show the effects of deAND supplementation on HFHC diet-induced apoptosis (b) in the liver. Glyceraldehyde 3-phosphate dehydrogenase (GADPH) served as the loading control. Active caspase 3, derived from cleavages of pro-caspase 3, was quantitated by the sum of 17 and 20 kd protein bands. The values are given as the mean ± S.D. (n = 3). * Significantly different from the Control group, p < 0.05. # Significantly different from the HFHC group, p < 0.05.
Figure 4
Figure 4
Effects of administrated of deAND on fecal cholesterol (a), and total bile acids (b) contents in rats. Results are expressed as the mean ± S.D. (n = 3). * Significantly different from the control group at p < 0.05. # Significantly different from HFHC group, p < 0.05. The feces in each group (six mice in one cage) was collected for three consecutive days and then the fecal cholesterol and bile acids from pooled samples in each group were determined in triplicates.
Figure 5
Figure 5
Western blotting analysis of NOD-like receptor protein 3 (NLRP3) and caspase-1 (P10) proteins in the liver (a). IL-1β protein level in liver was determined by a commercial kit as described in Material and Methods. The results show that deAND supplementation reduced the expressions of the proteins (n = 3 for figure b and c, and n = 6 for d) and mRNA (n = 6 for figure e–g) of NLRP3, caspase-1, and IL-1β in liver. The protein band was quantified by densitometry and mRNA expression level was calculated by the 2 -ΔΔCT method, respectively. * Significantly different from the Control group at p < 0.05. # Significantly different from the HFHC group, p < 0.05.
Figure 6
Figure 6
Effects of deAND supplementation on the hepatic TBARS content (a), GSH peroxidase activity (b), GSH reductase activity (c), pi form GSH-S-transferase (PGST) protein (d), HO-1 protein (e), and Nrf2 mRNA expression (f) in mice. Results are expressed as the mean ± S.D. (n = 6). * Significantly different from the Control group at p < 0.05. # Significantly different from HFHC group, p < 0.05. a Significantly different from the HFHC + 0.05% deAND group, p < 0.05.
Figure 7
Figure 7
Effects of deAND supplementation on glutamate levels in the plasma (a) and liver (b) in mice. Results are expressed as the mean ± S.D. (n = 6). * Significantly different from the Control group, p < 0.05. # Significantly different from the HFHC group, p < 0.05.
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