TY - JOUR
T1 - Hepatocyte ELOVL Fatty Acid Elongase 6 Determines Ceramide Acyl-Chain Length and Hepatic Insulin Sensitivity in Mice
AU - Matsuzaka, Takashi
AU - Kuba, Motoko
AU - Koyasu, Saori
AU - Yamamoto, Yuta
AU - Motomura, Kaori
AU - Arulmozhiraja, Sundaram
AU - Ohno, Hiroshi
AU - Sharma, Rahul
AU - Shimura, Takuya
AU - Okajima, Yuka
AU - Han, Song iee
AU - Aita, Yuichi
AU - Mizunoe, Yuhei
AU - Osaki, Yoshinori
AU - Iwasaki, Hitoshi
AU - Yatoh, Shigeru
AU - Suzuki, Hiroaki
AU - Sone, Hirohito
AU - Takeuchi, Yoshinori
AU - Yahagi, Naoya
AU - Miyamoto, Takafumi
AU - Sekiya, Motohiro
AU - Nakagawa, Yoshimi
AU - Ema, Masatsugu
AU - Takahashi, Satoru
AU - Tokiwa, Hiroaki
AU - Shimano, Hitoshi
N1 - Publisher Copyright:
© 2019 by the American Association for the Study of Liver Diseases.
PY - 2020/5/1
Y1 - 2020/5/1
N2 - Background and Aims: Dysfunctional hepatic lipid metabolism is a cause of nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disorder worldwide, and is closely associated with insulin resistance and type 2 diabetes. ELOVL fatty acid elongase 6 (Elovl6) is responsible for converting C16 saturated and monounsaturated fatty acids (FAs) into C18 species. We have previously shown that Elovl6 contributes to obesity-induced insulin resistance by modifying hepatic C16/C18-related FA composition. Approach and Results: To define the precise molecular mechanism by which hepatic Elovl6 affects energy homeostasis and metabolic disease, we generated liver-specific Elovl6 knockout (LKO) mice. Unexpectedly, LKO mice were not protected from high-fat diet–induced insulin resistance. Instead, LKO mice exhibited higher insulin sensitivity than controls when consuming a high-sucrose diet (HSD), which induces lipogenesis. Hepatic patatin-like phospholipase domain-containing protein 3 (Pnpla3) expression was down-regulated in LKO mice, and adenoviral Pnpla3 restoration reversed the enhancement in insulin sensitivity in HSD-fed LKO mice. Lipidomic analyses showed that the hepatic ceramide(d18:1/18:0) content was lower in LKO mice, which may explain the effect on insulin sensitivity. Ceramide(d18:1/18:0) enhances protein phosphatase 2A (PP2A) activity by interfering with the binding of PP2A to inhibitor 2 of PP2A, leading to Akt dephosphorylation. Its production involves the formation of an Elovl6–ceramide synthase 4 (CerS4) complex in the endoplasmic reticulum and a Pnpla3–CerS4 complex on lipid droplets. Consistent with this, liver-specific Elovl6 deletion in ob/ob mice reduced both hepatic ceramide(d18:1/18:0) and PP2A activity and ameliorated insulin resistance. Conclusions: Our study demonstrates the key role of hepatic Elovl6 in the regulation of the acyl-chain composition of ceramide and that C18:0-ceramide is a potent regulator of hepatic insulin signaling linked to Pnpla3-mediated NAFLD.
AB - Background and Aims: Dysfunctional hepatic lipid metabolism is a cause of nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disorder worldwide, and is closely associated with insulin resistance and type 2 diabetes. ELOVL fatty acid elongase 6 (Elovl6) is responsible for converting C16 saturated and monounsaturated fatty acids (FAs) into C18 species. We have previously shown that Elovl6 contributes to obesity-induced insulin resistance by modifying hepatic C16/C18-related FA composition. Approach and Results: To define the precise molecular mechanism by which hepatic Elovl6 affects energy homeostasis and metabolic disease, we generated liver-specific Elovl6 knockout (LKO) mice. Unexpectedly, LKO mice were not protected from high-fat diet–induced insulin resistance. Instead, LKO mice exhibited higher insulin sensitivity than controls when consuming a high-sucrose diet (HSD), which induces lipogenesis. Hepatic patatin-like phospholipase domain-containing protein 3 (Pnpla3) expression was down-regulated in LKO mice, and adenoviral Pnpla3 restoration reversed the enhancement in insulin sensitivity in HSD-fed LKO mice. Lipidomic analyses showed that the hepatic ceramide(d18:1/18:0) content was lower in LKO mice, which may explain the effect on insulin sensitivity. Ceramide(d18:1/18:0) enhances protein phosphatase 2A (PP2A) activity by interfering with the binding of PP2A to inhibitor 2 of PP2A, leading to Akt dephosphorylation. Its production involves the formation of an Elovl6–ceramide synthase 4 (CerS4) complex in the endoplasmic reticulum and a Pnpla3–CerS4 complex on lipid droplets. Consistent with this, liver-specific Elovl6 deletion in ob/ob mice reduced both hepatic ceramide(d18:1/18:0) and PP2A activity and ameliorated insulin resistance. Conclusions: Our study demonstrates the key role of hepatic Elovl6 in the regulation of the acyl-chain composition of ceramide and that C18:0-ceramide is a potent regulator of hepatic insulin signaling linked to Pnpla3-mediated NAFLD.
UR - http://www.scopus.com/inward/record.url?scp=85079069961&partnerID=8YFLogxK
U2 - 10.1002/hep.30953
DO - 10.1002/hep.30953
M3 - 学術論文
C2 - 31529722
AN - SCOPUS:85079069961
SN - 0270-9139
VL - 71
SP - 1609
EP - 1625
JO - Hepatology
JF - Hepatology
IS - 5
ER -