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. 2013 Oct 21;8(10):e77817.
doi: 10.1371/journal.pone.0077817. eCollection 2013.

Aliskiren attenuates steatohepatitis and increases turnover of hepatic fat in mice fed with a methionine and choline deficient diet

Kuei-Chuan Lee  1 , Che-Chang Chan, Ying-Ying Yang, Yun-Cheng Hsieh, Yi-Hsiang Huang, Han-Chieh Lin
Affiliations

Aliskiren attenuates steatohepatitis and increases turnover of hepatic fat in mice fed with a methionine and choline deficient diet

Kuei-Chuan Lee et al. PLoS One. .

Abstract

Background & aims: Activation of the renin-angiotensin-system is known to play a role in nonalcoholic steatohepatitis. Renin knockout mice manifest decreased hepatic steatosis. Aliskiren is the first direct renin inhibitor to be approved for clinical use. Our study aims to evaluate the possible therapeutic effects and mechanism of the chronic administration of aliskiren in a dietary steatohepatitis murine model.

Methods: Male C57BL/6 mice were fed with a methionine and choline-deficient (MCD) diet to induce steatohepatitis. After 8 weeks of feeding, the injured mice were randomly assigned to receive aliskiren (50 mg·kg(-1) per day) or vehicle administration for 4 weeks. Normal controls were also administered aliskiren (50 mg·kg(-1) per day) or a vehicle for 4 weeks.

Results: In the MCD mice, aliskiren attenuated hepatic steatosis, inflammation and fibrosis. Aliskiren did not change expression of lipogenic genes but increase turnover of hepatic fat by up-regulating peroxisome proliferator-activated receptor α, carnitine palmitoyltransferase 1a, cytochrome P450-4A14 and phosphorylated AMP-activated protein kinase. Furthermore, aliskiren decreased the hepatic expression of angiotensin II and nuclear factor κB. The levels of oxidative stress, hepatocyte apoptosis, activation of Kupffer cells and hepatic stellate cells, and pro-fibrotic markers were also reduced in the livers of the MCD mice receiving aliskiren.

Conclusions: Aliskiren attenuates steatohepatitis and fibrosis in mice fed with a MCD diet. Thus, the noted therapeutic effects might come from not only the reduction of angiotensin II but also the up-regulation of fatty acid oxidation-related genes.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Aliskiren (Ali) decreased expression of angiotensin II (Ang II) and attenuated steatosis and inflammation in the livers of mice fed with methionine choline deficiency (MCD) diet.
(A) Representative immunohistochemistry photomicrographs (×200) of hepatic Ang II and (B) the oil red O stain in all groups with quantification of the positive stained areas to the below. Scale bar = 100 μm. The haematoxylin and eosin (H&E) stain (C) and hepatic triglyceride (TG) content (D) in four groups. N-V/N-Ali: normal (N) mice receiving vehicle (V) or aliskiren; MCD-V/MCD-Ali: MCD mice treated with vehicle or aliskiren (##: P<0.01 vs. N-V; *: P<0.05 vs. MCD-V; **: P<0.01 vs. MCD-V).
Figure 2
Figure 2. Aliskiren increased turnover of triglyceride.
The transcript expression of sterol regulatory element binding protein-1 (SREBP1), carbohydrate responsive element binding protein (ChREBP), peroxisome proliferator-activated receptor gamma (PPAR-γ), fatty acid transport protein 1 and 4 (FATP1, FATP4), peroxisome proliferator-activated receptor alpha (PPARα), carnitine palmitoyltransferase 1a (CPT 1a), cytochrome P450-4A14 (CYP4A14), and cytochrome P450-4A10 (CYP4A10) in the livers of the four groups. N-V/N-Ali: normal (N) mice receiving vehicle (V) or aliskiren; MCD-V/MCD-Ali: MCD mice treated with vehicle or aliskiren #: p<0.05 vs. N-V; ##: p<0.01 vs. N-V; **: p<0.01 vs. MCD-V.
Figure 3
Figure 3. Aliskiren (Ali) up-regulated phosphorylation of AMPK and Akt but down-regulated expression of NF-κB p65 protein in mice fed with a methionine choline-deficient (MCD) diet.
Western blotting of hepatic phosphorylated/total AMP-activated protein kinase (p-AMPK/t-AMPK) (A) and Akt (p-Akt/t-Akt) (B). (C) Representative images of nuclear translocation of p65 in the four groups. N-V/N-Ali: normal (N) mice receiving vehicle (V) or aliskiren; MCD-V/MCD-Ali: MCD mice treated with vehicle or aliskiren. Scale bar = 100 μm.
Figure 4
Figure 4. Aliskiren (Ali) reduced oxidative stress, hepatocyte apoptosis and Kupffer cells activation in mice fed with a methionine choline-deficient (MCD) diet.
(A) The amount of thiobarbituric acid reactive substances (TBARS) and (B) expression of catalase, glutathione peroxidase-1 (GPX1) and superoxide dismutase-1 (SOD1) in the N-V (white bar), N-Ali (gray bar), MCD-V (black bar) and MCD-Ali (striped bar) groups. Representative images (×200) of phosphorylated p47 phox (p-p47 phox) (C), the terminal deoxynucleotide transferase mediated dUTP nick-end labeling (TUNEL) assay (D), and F4/80 (E) and quantification of positive stained areas (p-p47 phox and TUNEL) or cell counts (F4/80) per field of view to the below in all groups. Scale bar = 100 μm. N-V/N-Ali: normal (N) mice receiving vehicle (V) or aliskiren; MCD-V/MCD-Ali: MCD mice treated with vehicle or aliskiren. (#: P<0.05 vs. N-V; ##: P<0.01 vs. N-V; *: P<0.05 vs. MCD-V; **: P<0.01 vs. MCD-V).
Figure 5
Figure 5. Aliskiren (Ali) reduced hepatic stellate cells activation, collagen deposition and gene expression of pro-fibrotic markers in mice fed with a methionine choline-deficient (MCD) diet.
(A) Hepatic gene expression of alpha smooth muscle actin (α-SMA), collagen type I alpha 1 (COL1α1) and tissue inhibitor of metalloproteinases type I (TIMP-1) in the four groups. (B) Representative images (×200) of Masson's trichrome stain and α-SMA immunohistochemistry stain (C) in the livers. Scale bar = 100 μm. N-V/N-Ali: normal (N) mice receiving vehicle (V) or aliskiren; MCD-V/MCD-Ali: MCD mice treated with vehicle or aliskiren. (#: P<0.05 vs. N-V; ##: P<0.01 vs. N-V; *: P<0.05 vs. MCD-V; **: P<0.01 vs. MCD-V).
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This work was supported by grant NSC 101-2314-B-075-017 from the National Science Council of Taiwan and grant V102B-017 and V102C-014 from the Taipei Veterans General Hospital, Taipei, Taiwan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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