title: Absence of Elovl6 attenuates steatohepatitis but promotes gallstone formation in a lithogenic diet-fed Ldlr(-/-) mouse model.
abstract: Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) that can develop into liver cirrhosis and cancer. Elongation of very long chain fatty acids (ELOVL) family member 6 (Elovl6) is a microsomal enzyme that regulates the elongation of C12-16 saturated and monounsaturated fatty acids (FAs). We have previously shown that Elovl6 plays an important role in the development of hepatic insulin resistance and NASH by modifying FA composition. Recent studies have linked altered hepatic cholesterol homeostasis and cholesterol accumulation to the pathogenesis of NASH. In the present study, we further investigated the role of Elovl6 in the progression of lithogenic diet (LD)-induced steatohepatitis. We showed that the absence of Elovl6 suppresses hepatic lipid accumulation, plasma total cholesterol and total bile acid (BA) levels in LDL receptor-deficient (Ldlr(-/-)) mice challenged with a LD. The absence of Elovl6 also decreases hepatic inflammation, oxidative stress and liver injury, but increases the formation of cholesterol crystals in the less dilated gallbladder. These findings suggest that Elovl6-mediated changes in hepatic FA composition, especially oleic acid (C18:1n-9), control handling of hepatic cholesterol and BA, which protects against hepatotoxicity and steatohepatitis, but promotes gallstone formation in LD-fed Ldlr(-/-) mice.
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Motoko
authors.initials: M
authors.lastname: Kuba
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsuzaka
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Matsumori
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Saito
authors.affiliation: Laboratory of Proteomics and Biomolecular Science, Biomedical Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Kaga
authors.affiliation: Laboratory of Proteomics and Biomolecular Science, Biomedical Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Hikari
authors.initials: H
authors.lastname: Taka
authors.affiliation: Faculty of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Ikehata
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Naduki
authors.initials: N
authors.lastname: Okada
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Kikuchi
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohno
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Song-Iee
authors.initials: SI
authors.lastname: Han
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Takeuchi
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Iwasaki
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yatoh
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, Niigata University, 1-754 Asahimachi, Niigata 951-8510, Japan.
authors.forename: Hirohito
authors.initials: H
authors.lastname: Sone
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Yahagi
authors.affiliation: Faculty of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Arakawa
authors.affiliation: Laboratory of Proteomics and Biomolecular Science, Biomedical Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Fujimura
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.|International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Nakagawa
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Yamada
authors.affiliation: Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.|International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Shimano
mesh_terms: D000123:Acetyltransferases / Q000172:deficiency* / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism; D004032:Diet / Q000009:adverse effects*; D004195:Disease Models, Animal; D000081031:Fatty Acid Elongases; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D042882:Gallstones / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D011973:Receptors, LDL / Q000172:deficiency* / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; C000630968:Elovl6 protein, mouse; D011973:Receptors, LDL; D002784:Cholesterol; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases