Journal
HEPATOLOGY
Volume 71, Issue 5, Pages 1609-1625Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1002/hep.30953
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Funding
- AMED-CREST from the Japan Agency for Medical Research and Development, AMED
- Ministry of Science, Education, Culture, and Technology of Japan [15H02541, 18H04051, 17H06395, 15H03093, 18H03189]
- Japan Foundation for Applied Enzymology (Front Runner of Future Diabetes Research)
- Ono Medical Research Foundation
- Takeda Science Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Kowa Life Science Foundation
- Ministry of Science, Education, Culture, and Technology of Japan (Program to Disseminate Tenure Tracking System)
- Grants-in-Aid for Scientific Research [17H06395, 18H04051, 15H02541, 15H03093, 18H03189] Funding Source: KAKEN
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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.
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