TRIF Differentially Regulates Hepatic Steatosis and Inflammation/Fibrosis in Mice

Ling Yang; Kouichi Miura; Bi Zhang; Hiroshi Matsushita; Yoon Mee Yang; Shuang Liang; Jingyi Song; Yoon Seok Roh; Ekihiro Seki

doi:10.1016/j.jcmgh.2016.12.004

TRIF Differentially Regulates Hepatic Steatosis and Inflammation/Fibrosis in Mice

Cell Mol Gastroenterol Hepatol. 2017 Jan 17;3(3):469-483. doi: 10.1016/j.jcmgh.2016.12.004. eCollection 2017 May.

Authors

Ling Yang^{1

2}, Kouichi Miura^{1

3}, Bi Zhang¹, Hiroshi Matsushita^{1

4}, Yoon Mee Yang⁴, Shuang Liang¹, Jingyi Song¹, Yoon Seok Roh^{1

4

5}, Ekihiro Seki^{1

4

6

7}

Affiliations

¹ Division of Gastroenterology, Department of Medicine, University of California San Diego, School of Medicine, La Jolla, California.
² Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
³ Department of Gastroenterology, Akita University Graduate School of Medicine, Akita, Japan.
⁴ Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
⁵ Department of Pharmacy, Chungbuk National University College of Pharmacy, Chungbuk, South Korea.
⁶ Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California.
⁷ Department of Medicine, University of California Los Angeles, David Geffen School of Medicine, Los Angeles, California.

Abstract

Background & aims: Toll-like receptor 4 (TLR4) signaling is activated through 2 adaptor proteins: MyD88 and TIR-domain containing adaptor-inducing interferon-β (TRIF). TLR4 and MyD88 are crucial in nonalcoholic steatohepatitis (NASH) and fibrosis. However, the role of TRIF in TLR4-mediated NASH and fibrosis has been elusive. This study investigated the differential roles of TRIF in hepatic steatosis and inflammation/fibrosis.

Methods: A choline-deficient amino acid defined (CDAA) diet was used for the mouse NASH model. On this diet, the mice develop hepatic steatosis, inflammation, and fibrosis. TLR4 wild-type and TLR4^-/- bone marrow chimeric mice and TRIF^-/- mice were fed CDAA or a control diet for 22 weeks. Hepatic steatosis, inflammation, and fibrosis were examined.

Results: In the CDAA diet-induced NASH, the mice with wild-type bone marrow had higher alanine aminotransferase and hepatic tumor necrosis factor levels than the mice with TLR4^-/- bone marrow. The nonalcoholic fatty liver disease activity score showed that both wild-type and TLR4^-/- bone marrow chimeras had reduced hepatic steatosis, and that both types of chimeras had similar levels of inflammation and hepatocyte ballooning to whole-body wild-type mice. Notably, wild-type recipients showed more liver fibrosis than TLR4^-/- recipients. Although TRIF^-/- mice showed reduced hepatic steatosis, these mice showed more liver injury, inflammation, and fibrosis than wild-type mice. TRIF^-/- stellate cells and hepatocytes produced more C-X-C motif chemokine ligand 1 (CXCL1) and C-C motif chemokine ligand than wild-type cells in response to lipopolysaccharide. Consistently, TRIF^-/- mice showed increased CXCL1 and CCL3 expression along with neutrophil and macrophage infiltration, which promotes liver inflammation and injury.

Conclusions: In TLR4-mediated NASH, different liver cells have distinct roles in hepatic steatosis, inflammation, and fibrosis. TRIF promotes hepatic steatosis but it inhibits injury, inflammation, and fibrosis.

Keywords: ALT, alanine aminotransferase; BM, bone marrow; BMT, bone marrow transplantation; CDAA, choline-deficient amino acid defined; DGAT2, diacylglycerol acyltransferase 2; HFD, high-fat diet; HSC, hepatic stellate cell; Hepatocyte Apoptosis; IL, interleukin; LDH, lactate dehydrogenase; LPS; LPS, lipopolysaccharide; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; Neutrophils; PCR, polymerase chain reaction; TLR4; TLR4, Toll-like receptor 4; TNF, tumor necrosis factor; α-SMA, α-smooth muscle actin.

Abstract

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