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Bofutsushosan, a Japanese herbal (Kampo) medicine, attenuates progression of nonalcoholic steatohepatitis in mice.

Ono M, Ogasawara M, Hirose A, Mogami S, Ootake N, Aritake K, Higuchi T, Okamoto N, Sakamoto S, Yamamoto M, Urade Y, Saibara T, Oben JA - J. Gastroenterol. (2013)

Bottom Line: The effectiveness of BTS in attenuating features of NASH and the mechanisms through which BTS attenuated NASH were then assayed through an assessment of the anthropometric, radiological, biochemical and histological parameters.BTS attenuated the progression of NASH through induction of adiponectin and its receptors along with an induction of PPAR-α and PPAR-γ, decreased expression of SREBP-1c, increased hepatic fatty acid oxidation and increased hepatic export of triglycerides.BTS moreover, reduced IR through phosphorylation of the protein kinase, Akt.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology and Hepatology, Kochi Medical School, Kohasu, Nankoku, Kochi, 783-8505, Japan, onom@kochi-u.ac.jp.

ABSTRACT

Background: Obesity-induced liver disease (nonalcoholic fatty liver disease, NAFLD) is now the commonest cause of chronic liver disease in affluent nations. There are presently no proven treatments for NAFLD or its more severe stage, nonalcoholic steatohepatitis (NASH). Bofutsushosan (BTS), a Japanese herbal (Kampo) medicine, long used as an anti-obesity medicine in Japan and other Asian countries, has been shown to reduce body weight and improve insulin resistance (IR) and hepatic steatosis. The precise mechanism of action of BTS, however, remains unclear. To evaluate the ability of BTS to prevent the development of NASH, and determine the mediators and pathways involved.

Methods: C57BL/6 mice were injected intra-peritoneally with gold-thioglucose and fed a high-fat diet (HF) or HF diet admixed with either 2 or 5 % BTS for 12 weeks. The effectiveness of BTS in attenuating features of NASH and the mechanisms through which BTS attenuated NASH were then assayed through an assessment of the anthropometric, radiological, biochemical and histological parameters.

Results: BTS attenuated the progression of NASH through induction of adiponectin and its receptors along with an induction of PPAR-α and PPAR-γ, decreased expression of SREBP-1c, increased hepatic fatty acid oxidation and increased hepatic export of triglycerides. BTS moreover, reduced IR through phosphorylation of the protein kinase, Akt.

Conclusions: BTS through induction of adiponectin signaling and Akt attenuated development of NASH. Identification of the active entity in BTS should allow development of novel treatments for NASH.

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Related in: MedlinePlus

BTS attenuates hepatosteatosis through activation of adiponectin. a Plasma adiponectin and expression of adiponectin receptors 1 (AdipoR1) and 2 (AdipoR2): plasma adiponectin levels and hepatic mRNA expression of AdipoR1 and AdipoR2 were dose dependently increased by BTS. Asteriskp < 0.05, triple asteriskp < 0.001 vs GTG + HF, n = 6. b–d AdioR1 signaling and target genes expression: BTS induced AdipoR1 signaling suppressed nuclear expression of SREBP-1c (n = 4) through phosphorylated AMPK (n = 4). Expression of PPAR-γ mRNA was also increased by BTS treatment (n = 6). Asteriskp < 0.05, doubleasteriskp < 0.01 vs GTG + HF. e–g Expression of PPAR-α and its target genes: Expression of PPAR-α mRNA was increase by BTS (n = 6). Expression of MCAD (n = 6) and CYP2E1 (n = 6), PPAR-α target genes, was similarly increased by BTS. Asteriskp < 0.05, doubleasteriskp < 0.01, tripleasteriskp < 0.001 vs GTG + HF. h, i BTS promotes hepatic lipid export: MRNA expression of MTP (n = 6) and DGAT2 (n = 6) was increased by treatment with BTS. Asteriskp < 0.05 vs GTG + HF
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Fig4: BTS attenuates hepatosteatosis through activation of adiponectin. a Plasma adiponectin and expression of adiponectin receptors 1 (AdipoR1) and 2 (AdipoR2): plasma adiponectin levels and hepatic mRNA expression of AdipoR1 and AdipoR2 were dose dependently increased by BTS. Asteriskp < 0.05, triple asteriskp < 0.001 vs GTG + HF, n = 6. b–d AdioR1 signaling and target genes expression: BTS induced AdipoR1 signaling suppressed nuclear expression of SREBP-1c (n = 4) through phosphorylated AMPK (n = 4). Expression of PPAR-γ mRNA was also increased by BTS treatment (n = 6). Asteriskp < 0.05, doubleasteriskp < 0.01 vs GTG + HF. e–g Expression of PPAR-α and its target genes: Expression of PPAR-α mRNA was increase by BTS (n = 6). Expression of MCAD (n = 6) and CYP2E1 (n = 6), PPAR-α target genes, was similarly increased by BTS. Asteriskp < 0.05, doubleasteriskp < 0.01, tripleasteriskp < 0.001 vs GTG + HF. h, i BTS promotes hepatic lipid export: MRNA expression of MTP (n = 6) and DGAT2 (n = 6) was increased by treatment with BTS. Asteriskp < 0.05 vs GTG + HF

Mentions: We examined plasma adiponectin levels and liver expression of the adiponectin receptors (AdipoR1 and AdipoR2), an important anti-inflammatory cytokine and receptors [18–20], because both plasma adiponectin levels and liver expression of the adiponectin receptors were decreased in GTG + HF mice as described previously [9]. Plasma adiponectin level and hepatic expression of AdipoR1, R2 were significantly enhanced by BTS (Fig. 4a). We next investigated the pathways of suppression of hepatic lipid metabolism by adiponectin in the presence of BTS. The expression of SREBP-1c was decreased dose dependently by BTS (Fig. 4b). The phosphorylation of AMPK (P-AMPK/AMPK) was here increased by BTS treatment (Fig. 4c) in parallel with activation of AdipoR1 signaling (Fig. 4a). In addition, expression of PPAR-γ, an activator of AMPK, was increased by BTS treatment (Fig. 4d).Fig. 4


Bofutsushosan, a Japanese herbal (Kampo) medicine, attenuates progression of nonalcoholic steatohepatitis in mice.

Ono M, Ogasawara M, Hirose A, Mogami S, Ootake N, Aritake K, Higuchi T, Okamoto N, Sakamoto S, Yamamoto M, Urade Y, Saibara T, Oben JA - J. Gastroenterol. (2013)

BTS attenuates hepatosteatosis through activation of adiponectin. a Plasma adiponectin and expression of adiponectin receptors 1 (AdipoR1) and 2 (AdipoR2): plasma adiponectin levels and hepatic mRNA expression of AdipoR1 and AdipoR2 were dose dependently increased by BTS. Asteriskp < 0.05, triple asteriskp < 0.001 vs GTG + HF, n = 6. b–d AdioR1 signaling and target genes expression: BTS induced AdipoR1 signaling suppressed nuclear expression of SREBP-1c (n = 4) through phosphorylated AMPK (n = 4). Expression of PPAR-γ mRNA was also increased by BTS treatment (n = 6). Asteriskp < 0.05, doubleasteriskp < 0.01 vs GTG + HF. e–g Expression of PPAR-α and its target genes: Expression of PPAR-α mRNA was increase by BTS (n = 6). Expression of MCAD (n = 6) and CYP2E1 (n = 6), PPAR-α target genes, was similarly increased by BTS. Asteriskp < 0.05, doubleasteriskp < 0.01, tripleasteriskp < 0.001 vs GTG + HF. h, i BTS promotes hepatic lipid export: MRNA expression of MTP (n = 6) and DGAT2 (n = 6) was increased by treatment with BTS. Asteriskp < 0.05 vs GTG + HF
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Fig4: BTS attenuates hepatosteatosis through activation of adiponectin. a Plasma adiponectin and expression of adiponectin receptors 1 (AdipoR1) and 2 (AdipoR2): plasma adiponectin levels and hepatic mRNA expression of AdipoR1 and AdipoR2 were dose dependently increased by BTS. Asteriskp < 0.05, triple asteriskp < 0.001 vs GTG + HF, n = 6. b–d AdioR1 signaling and target genes expression: BTS induced AdipoR1 signaling suppressed nuclear expression of SREBP-1c (n = 4) through phosphorylated AMPK (n = 4). Expression of PPAR-γ mRNA was also increased by BTS treatment (n = 6). Asteriskp < 0.05, doubleasteriskp < 0.01 vs GTG + HF. e–g Expression of PPAR-α and its target genes: Expression of PPAR-α mRNA was increase by BTS (n = 6). Expression of MCAD (n = 6) and CYP2E1 (n = 6), PPAR-α target genes, was similarly increased by BTS. Asteriskp < 0.05, doubleasteriskp < 0.01, tripleasteriskp < 0.001 vs GTG + HF. h, i BTS promotes hepatic lipid export: MRNA expression of MTP (n = 6) and DGAT2 (n = 6) was increased by treatment with BTS. Asteriskp < 0.05 vs GTG + HF
Mentions: We examined plasma adiponectin levels and liver expression of the adiponectin receptors (AdipoR1 and AdipoR2), an important anti-inflammatory cytokine and receptors [18–20], because both plasma adiponectin levels and liver expression of the adiponectin receptors were decreased in GTG + HF mice as described previously [9]. Plasma adiponectin level and hepatic expression of AdipoR1, R2 were significantly enhanced by BTS (Fig. 4a). We next investigated the pathways of suppression of hepatic lipid metabolism by adiponectin in the presence of BTS. The expression of SREBP-1c was decreased dose dependently by BTS (Fig. 4b). The phosphorylation of AMPK (P-AMPK/AMPK) was here increased by BTS treatment (Fig. 4c) in parallel with activation of AdipoR1 signaling (Fig. 4a). In addition, expression of PPAR-γ, an activator of AMPK, was increased by BTS treatment (Fig. 4d).Fig. 4

Bottom Line: The effectiveness of BTS in attenuating features of NASH and the mechanisms through which BTS attenuated NASH were then assayed through an assessment of the anthropometric, radiological, biochemical and histological parameters.BTS attenuated the progression of NASH through induction of adiponectin and its receptors along with an induction of PPAR-α and PPAR-γ, decreased expression of SREBP-1c, increased hepatic fatty acid oxidation and increased hepatic export of triglycerides.BTS moreover, reduced IR through phosphorylation of the protein kinase, Akt.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology and Hepatology, Kochi Medical School, Kohasu, Nankoku, Kochi, 783-8505, Japan, onom@kochi-u.ac.jp.

ABSTRACT

Background: Obesity-induced liver disease (nonalcoholic fatty liver disease, NAFLD) is now the commonest cause of chronic liver disease in affluent nations. There are presently no proven treatments for NAFLD or its more severe stage, nonalcoholic steatohepatitis (NASH). Bofutsushosan (BTS), a Japanese herbal (Kampo) medicine, long used as an anti-obesity medicine in Japan and other Asian countries, has been shown to reduce body weight and improve insulin resistance (IR) and hepatic steatosis. The precise mechanism of action of BTS, however, remains unclear. To evaluate the ability of BTS to prevent the development of NASH, and determine the mediators and pathways involved.

Methods: C57BL/6 mice were injected intra-peritoneally with gold-thioglucose and fed a high-fat diet (HF) or HF diet admixed with either 2 or 5 % BTS for 12 weeks. The effectiveness of BTS in attenuating features of NASH and the mechanisms through which BTS attenuated NASH were then assayed through an assessment of the anthropometric, radiological, biochemical and histological parameters.

Results: BTS attenuated the progression of NASH through induction of adiponectin and its receptors along with an induction of PPAR-α and PPAR-γ, decreased expression of SREBP-1c, increased hepatic fatty acid oxidation and increased hepatic export of triglycerides. BTS moreover, reduced IR through phosphorylation of the protein kinase, Akt.

Conclusions: BTS through induction of adiponectin signaling and Akt attenuated development of NASH. Identification of the active entity in BTS should allow development of novel treatments for NASH.

Show MeSH
Related in: MedlinePlus