Lipoprotein Lipase Up-regulation in Hepatic Stellate Cells Exacerbates Liver Fibrosis in Nonalcoholic Steatohepatitis in Mice.

Abstract

Lipoprotein lipase (LPL) plays a central role in incorporating plasma lipids into tissues and regulates lipid metabolism and energy balance in the human body. Conversely, LPL expression is almost absent in normal adult livers. Therefore, its physiological role in the liver remains unknown. We aimed to elucidate the role of LPL in the pathophysiology of nonalcoholic steatohepatitis (NASH), a hepatic manifestation of obesity. Hepatic stellate cell (HSC)-specific LPL-knockout (LplHSC-KO ) mice, LPL-floxed (Lplfl/fl ) mice, or double-mutant toll-like receptor 4-deficient (Tlr4-/- ) LplHSC-KO mice were fed a high-fat/high-cholesterol diet for 4 weeks to establish the nonalcoholic fatty liver model or an high-fat/high-cholesterol diet for 24 weeks to establish the NASH model. Human samples, derived from patients with nonalcoholic fatty liver disease, were also examined. In human and mouse NASH livers, serum obesity-related factors, such as free fatty acid, leptin, and interleukin-6, dramatically increased the expression of LPL, specifically in HSCs through signal transducer and activator of transcription 3 signaling, as opposed to that in hepatocytes or hepatic macrophages. In the NASH mouse model, liver fibrosis was significantly reduced in LplHSC-KO mice compared with that in Lplfl/fl mice. Nonenzymatic LPL-mediated cholesterol uptake from serum lipoproteins enhanced the accumulation of free cholesterol in HSCs, which amplified TLR4 signaling, resulting in the activation of HSCs and progression of hepatic fibrosis in NASH. Conclusion: The present study reveals the pathophysiological role of LPL in the liver, and furthermore, clarifies the pathophysiology in which obesity, as a background factor, exacerbates NASH. The LPL-mediated HSC activation pathway could be a promising therapeutic target for treating liver fibrosis in NASH.

• Authors: Toshiaki Teratani, Kengo Tomita, Hirotaka Furuhashi, Nao Sugihara, Masaaki Higashiyama, Makoto Nishikawa, Rie Irie, Takeshi Takajo, Akinori Wada, Kazuki Horiuchi, Kenichi Inaba, Yoshinori Hanawa, Naoki Shibuya, Yoshikiyo Okada, Chie Kurihara, Shin Nishii, Akinori Mizoguchi, Hideaki Hozumi, Chikako Watanabe, Shunsuke Komoto, Shigeaki Nagao, Junji Yamamoto, Soichiro Miura, Ryota Hokari, Tananori Kanai
• Journal: Hepatology communications (Hepatol Commun) Vol. 3 Issue 8 Pg. 1098-1112 (Aug 2019) ISSN: 2471-254X [Electronic] United States
• PMID: 31388630 (Publication Type: Journal Article)