title: The serine protease prostasin regulates hepatic insulin sensitivity by modulating TLR4 signalling.
abstract: The effects of high-fat diet (HFD) and postprandial endotoxemia on the development of type 2 diabetes are not fully understood. Here we show that the serine protease prostasin (PRSS8) regulates hepatic insulin sensitivity by modulating Toll-like receptor 4 (TLR4)-mediated signalling. HFD triggers the suppression of PRSS8 expression by inducing endoplasmic reticulum (ER) stress and increases the TLR4 level in the liver. PRSS8 releases the ectodomain of TLR4 by cleaving it, which results in a reduction in the full-length form and reduces the activation of TLR4. Liver-specific PRSS8 knockout (LKO) mice develop insulin resistance associated with the increase in hepatic TLR4. Restoration of PRSS8 expression in livers of HFD, LKO and db/db mice decreases the TLR4 level and ameliorates insulin resistance. These results identify a novel physiological role for PRSS8 in the liver and provide new insight into the development of diabetes resulting from HFD or metabolic endotoxemia.
authors.affiliation: 1] Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto 860-8556, Japan [2].
authors.forename: Kohei
authors.initials: K
authors.lastname: Uchimura
authors.affiliation: 1] Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto 860-8556, Japan [2].
authors.forename: Manabu
authors.initials: M
authors.lastname: Hayata
authors.affiliation: 1] Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto 860-8556, Japan [2].
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Mizumoto
authors.affiliation: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto 860-8556, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Miyasato
authors.affiliation: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto 860-8556, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kakizoe
authors.affiliation: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto 860-8556, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Morinaga
authors.affiliation: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto 860-8556, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Onoue
authors.affiliation: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto 860-8556, Japan.
authors.forename: Rika
authors.initials: R
authors.lastname: Yamazoe
authors.affiliation: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto 860-8556, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Ueda
authors.affiliation: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto 860-8556, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Adachi
authors.affiliation: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto 860-8556, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Miyoshi
authors.affiliation: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto 860-8556, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Shiraishi
authors.affiliation: Department of Medicine, Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Ogawa
authors.affiliation: Department of Metabolic Medicine, Kumamoto University Graduate School of Medical Sciences, Kumamoto 860-8556, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Fukuda
authors.affiliation: Department of Metabolic Medicine, Kumamoto University Graduate School of Medical Sciences, Kumamoto 860-8556, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kondo
authors.affiliation: Department of Metabolic Medicine, Kumamoto University Graduate School of Medical Sciences, Kumamoto 860-8556, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Matsumura
authors.affiliation: Department of Metabolic Medicine, Kumamoto University Graduate School of Medical Sciences, Kumamoto 860-8556, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Araki
authors.affiliation: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto 860-8556, Japan.
authors.forename: Kimio
authors.initials: K
authors.lastname: Tomita
authors.affiliation: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto 860-8556, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Kitamura
mesh_terms: D000818:Animals; D015992:Body Mass Index; D002462:Cell Membrane / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D004721:Endoplasmic Reticulum / Q000378:metabolism; D018149:Glucose Intolerance / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D000099271:Prostasin
chemical_list: D012697:Serine Endopeptidases; D051197:Toll-Like Receptor 4; D000099271:Prostasin; C493487:Tlr4 protein, mouse