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Biochem Biophys Res Commun. 2018 Mar 18;497(4):957-962. doi: 10.1016/j.bbrc.2018.01.191. Epub 2018 Feb 2.

Loss of toll-like receptor 3 aggravates hepatic inflammation but ameliorates steatosis in mice.

Author information

1
Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea.
2
Department of Pharmacology, School of Dentistry, Brain Science and Engineering Institute, Kyungpook National University, Daegu, 41940, Republic of Korea.
3
Department of Pharmacology, School of Dentistry, Kyungpook National University, Daegu, 41940, Republic of Korea.
4
Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141, Republic of Korea.
5
Department of Oral Medicine, School of Dentistry, Kyungpook National University, Daegu, 41940, Republic of Korea.
6
Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, 305-764, Republic of Korea. Electronic address: jmpbooks@cnuh.co.kr.
7
Department of Oral Medicine, School of Dentistry, Kyungpook National University, Daegu, 41940, Republic of Korea. Electronic address: jsbyun@knu.ac.kr.

Abstract

The importance of toll-like receptor (TLR) 4 in the pathogenesis of steatohepatitis has been well documented; however, little is known about the role of TLR3. In this study, we determined whether the depletion of TLR3 modulated hepatic injury in mice and further aimed to provide mechanistic insights into the TLR3-mediated modulation of diet-induced hepatic inflammation and fat accumulation. Hepatic steatosis and inflammatory response were induced by feeding wild-type (WT) or TLR3 knockout mice a high-fat diet for 8 weeks. Primary liver resident cells, including hepatocytes, Kupffer cells, and hepatic stellate cells (HSCs), were treated with palmitic acid. TLR3 knockout mice fed a high-fat diet showed severe hepatic inflammation accompanied by nuclear factor-κB and IRF3 activation, which is mainly induced by the activation of Kupffer cells. Decreased TLR4 expression was restored in hepatic mononuclear cells and Kupffer cells in TLR3 knockout mice compared to that in the WT. Moreover, hepatic steatosis was decreased in TLR3 knockout mice. Hepatocytes from TLR3 knockout mice exhibited reduced expression of cannabinoid receptors. HSCs from TLR3 knockout mice showed decreased expression of the enzymes involved in endocannabinoid synthesis. In conclusion, this study suggests that the selective modulation of TLR3 could be a novel therapeutic target for the treatment of hepatic inflammation and steatosis.

KEYWORDS:

Endocannabinoids; Lipogenesis; Necroinflammations; Nonalcoholic steatohepatitis

PMID:
29410095
DOI:
10.1016/j.bbrc.2018.01.191
[Indexed for MEDLINE]

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