Carnosic acid (CA) prevents lipid accumulation in hepatocytes through the EGFR/MAPK pathway (original) (raw)

Abstract

Background

Carnosic acid (CA), found in rosemary, has been reported to have antioxidant and anti-adipogenic properties. We recently demonstrated that CA protects against steatosis in ob/ob mice. In the present report, we investigated the molecular mechanism by which CA inhibits lipids accumulation both in vivo and in vitro_._

Methods

In the in vivo study, ob/ob mice were fed a standard chow diet with or without CA for 5 weeks, then their hepatocyte lipid accumulation was determined. The serum concentrations of cytokines, the levels of lipid regulatory mediators, and the hepatic metabolic and signaling molecules were also evaluated. In the in vitro study, HepG2 cells were used to further clarify the effects of CA on cellular lipid accumulation and to confirm the signaling pathways involved in these effects.

Results

CA significantly reduced hepatocyte lipid accumulation. This effect was associated with repressed levels of hepatic PPARγ, reduced expression of inflammatory cytokines such as IL-1β, IL-12, IL-17, IFN-γ, MCP-1, and MIP-1β, and increased ATP, acetyl CoA, NAD(P)+, and NAD(P)H. Other signaling molecules, such as EGFR, MAPK, AMPK, and ACC, which regulate lipid metabolism, were activated in mice fed the CA diet. CA inhibited palmitate-induced cellular lipid accumulation and stimulated the phosphorylation of both EGFR and MAPK. Pretreatment with either the EGFR inhibitor AG1478 or the MEK-specific inhibitor U0126 abolished the effects of CA on cellular lipid accumulation and decreased both the protein expression and activity of PPARγ.

Conclusions

EGFR/MAPK signaling plays an important role in the inhibitory effect of CA on hepatocyte lipid accumulation.

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Abbreviations

ACC:

Acetyl CoA carboxylase

AMPK:

AMP-activated protein kinase

ATP:

Adenosine triphosphate

CA:

Carnosic acid

EGFR:

Epithelium growth factor receptor

FAS:

Fatty acid synthase

FFA:

Free fatty acid

G-CSF:

Granulocyte colony-stimulating factor

GMCSF:

Granulocyte macrophage colony-stimulating factor

GSH:

Glutathione

IFN:

Interferon

IL:

Interleukin

MAPK:

Mitogen-activated protein kinase

MCP-1:

Monocyte chemotactic protein

MIP:

Macrophage inflammatory protein

NAFLD:

Nonalcoholic fatty liver disease

NF-κB:

Nuclear factor-kappa B

PPAR:

Peroxisome proliferation activator receptor

SREBP-1:

Sterol regulatory element-binding protein-1

TG:

Triglyceride

TGFβ1:

Transforming growth factorβ1

TZDs:

Thiazolidinediones

UCP2:

Uncoupling protein 2

WAT:

White adipose tissue

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Acknowledgments

This study was supported by a Grant-in-Aid for Strategic Medical Science Research Center (S1001001) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. We thank Ms. A. Watanabe and Mr. K. Ishida for their valuable technical assistance.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Iwate Medical University, Morioka, Iwate, Japan
    Ting Wang, Yasuhiro Takikawa & Kazuyuki Suzuki
  2. Department of Welfare Engineering, Faculty of Engineering, Iwate University, Morioka, Iwate, Japan
    Takahito Tabuchi & Takumi Satoh
  3. Research and Development Center, Nagase Co., Ltd., Kobe, Japan
    Kunio Kosaka

Authors

  1. Ting Wang
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  2. Yasuhiro Takikawa
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  3. Takahito Tabuchi
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  4. Takumi Satoh
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  5. Kunio Kosaka
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  6. Kazuyuki Suzuki
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Corresponding author

Correspondence toYasuhiro Takikawa.

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Wang, T., Takikawa, Y., Tabuchi, T. et al. Carnosic acid (CA) prevents lipid accumulation in hepatocytes through the EGFR/MAPK pathway.J Gastroenterol 47, 805–813 (2012). https://doi.org/10.1007/s00535-012-0546-7

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