Free cholesterol accumulation in hepatic stellate cells: Mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice

Kengo Tomita, Toshiaki Teratani, Takahiro Suzuki, Motonori Shimizu, Hirokazu Sato, Kazuyuki Narimatsu, Yoshikiyo Okada, Chie Kurihara, Rie Irie, Hirokazu Yokoyama, Katsuyoshi Shimamura, Shingo Usui, Hirotoshi Ebinuma, Hidetsugu Saito, Chikako Watanabe, Shunsuke Komoto, Atsushi Kawaguchi, Shigeaki Nagao, Kazuo Sugiyama, Ryota HokariTakanori Kanai, Soichiro Miura, Toshifumi Hibi

Research output: Contribution to journalArticle

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Abstract

Although nonalcoholic steatohepatitis (NASH) is associated with hypercholesterolemia, the underlying mechanisms of this association have not been clarified. We aimed to elucidate the precise role of cholesterol in the pathophysiology of NASH. C57BL/6 mice were fed a control, high-cholesterol (HC), methionine-choline-deficient (MCD), or MCD+HC diet for 12 weeks or a control, HC, high-fat (HF), or HF+HC diet for 24 weeks. Increased cholesterol intake accelerated liver fibrosis in both the mouse models without affecting the degree of hepatocellular injury or Kupffer cell activation. The major causes of the accelerated liver fibrosis involved free cholesterol (FC) accumulation in hepatic stellate cells (HSCs), which increased Toll-like receptor 4 protein (TLR4) levels through suppression of the endosomal-lysosomal degradation pathway of TLR4, and thereby sensitized the cells to transforming growth factor (TGF)β-induced activation by down-regulating the expression of bone morphogenetic protein and activin membrane-bound inhibitor. Mammalian-cell cholesterol levels are regulated by way of a feedback mechanism mediated by sterol regulatory element-binding protein 2 (SREBP2), maintaining cellular cholesterol homeostasis. Nevertheless, HSCs were sensitive to FC accumulation because the high intracellular expression ratio of SREBP cleavage-activating protein (Scap) to insulin-induced gene (Insig) disrupted the SREBP2-mediated feedback regulation of cholesterol homeostasis in these cells. HSC activation subsequently enhanced the disruption of the feedback system by Insig-1 down-regulation. In addition, the suppression of peroxisome proliferator-activated receptor γ signaling accompanying HSC activation enhanced both SREBP2 and microRNA-33a signaling. Consequently, FC accumulation in HSCs increased and further sensitized these cells to TGFβ-induced activation in a vicious cycle, leading to exaggerated liver fibrosis in NASH. Conclusion: These characteristic mechanisms of FC accumulation in HSCs are potential targets to treat liver fibrosis in liver diseases including NASH.

Original languageEnglish
Pages (from-to)154-169
Number of pages16
JournalHepatology
Volume59
Issue number1
DOIs
Publication statusPublished - 2014 Jan 1

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Hepatic Stellate Cells
Liver Cirrhosis
Cholesterol
Sterol Regulatory Element Binding Protein 2
Toll-Like Receptor 4
Transforming Growth Factors
Choline
Methionine
Non-alcoholic Fatty Liver Disease
Homeostasis
Insulin
Activins
Bone Morphogenetic Proteins
Peroxisome Proliferator-Activated Receptors
Kupffer Cells
High Fat Diet
Hypercholesterolemia
MicroRNAs
Inbred C57BL Mouse
Genes

ASJC Scopus subject areas

  • Hepatology
  • Medicine(all)

Cite this

Free cholesterol accumulation in hepatic stellate cells : Mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice. / Tomita, Kengo; Teratani, Toshiaki; Suzuki, Takahiro; Shimizu, Motonori; Sato, Hirokazu; Narimatsu, Kazuyuki; Okada, Yoshikiyo; Kurihara, Chie; Irie, Rie; Yokoyama, Hirokazu; Shimamura, Katsuyoshi; Usui, Shingo; Ebinuma, Hirotoshi; Saito, Hidetsugu; Watanabe, Chikako; Komoto, Shunsuke; Kawaguchi, Atsushi; Nagao, Shigeaki; Sugiyama, Kazuo; Hokari, Ryota; Kanai, Takanori; Miura, Soichiro; Hibi, Toshifumi.

In: Hepatology, Vol. 59, No. 1, 01.01.2014, p. 154-169.

Research output: Contribution to journalArticle

Tomita, K, Teratani, T, Suzuki, T, Shimizu, M, Sato, H, Narimatsu, K, Okada, Y, Kurihara, C, Irie, R, Yokoyama, H, Shimamura, K, Usui, S, Ebinuma, H, Saito, H, Watanabe, C, Komoto, S, Kawaguchi, A, Nagao, S, Sugiyama, K, Hokari, R, Kanai, T, Miura, S & Hibi, T 2014, 'Free cholesterol accumulation in hepatic stellate cells: Mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice', Hepatology, vol. 59, no. 1, pp. 154-169. https://doi.org/10.1002/hep.26604
Tomita, Kengo ; Teratani, Toshiaki ; Suzuki, Takahiro ; Shimizu, Motonori ; Sato, Hirokazu ; Narimatsu, Kazuyuki ; Okada, Yoshikiyo ; Kurihara, Chie ; Irie, Rie ; Yokoyama, Hirokazu ; Shimamura, Katsuyoshi ; Usui, Shingo ; Ebinuma, Hirotoshi ; Saito, Hidetsugu ; Watanabe, Chikako ; Komoto, Shunsuke ; Kawaguchi, Atsushi ; Nagao, Shigeaki ; Sugiyama, Kazuo ; Hokari, Ryota ; Kanai, Takanori ; Miura, Soichiro ; Hibi, Toshifumi. / Free cholesterol accumulation in hepatic stellate cells : Mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice. In: Hepatology. 2014 ; Vol. 59, No. 1. pp. 154-169.
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AU - Tomita, Kengo

AU - Teratani, Toshiaki

AU - Suzuki, Takahiro

AU - Shimizu, Motonori

AU - Sato, Hirokazu

AU - Narimatsu, Kazuyuki

AU - Okada, Yoshikiyo

AU - Kurihara, Chie

AU - Irie, Rie

AU - Yokoyama, Hirokazu

AU - Shimamura, Katsuyoshi

AU - Usui, Shingo

AU - Ebinuma, Hirotoshi

AU - Saito, Hidetsugu

AU - Watanabe, Chikako

AU - Komoto, Shunsuke

AU - Kawaguchi, Atsushi

AU - Nagao, Shigeaki

AU - Sugiyama, Kazuo

AU - Hokari, Ryota

AU - Kanai, Takanori

AU - Miura, Soichiro

AU - Hibi, Toshifumi

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