Hepatocyte ELOVL Fatty Acid Elongase 6 Determines Ceramide Acyl-Chain Length and Hepatic Insulin Sensitivity in Mice.
Hepatology
; 71(5): 1609-1625, 2020 05.
Article
en En
| MEDLINE
| ID: mdl-31529722
ABSTRACT
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 ANDRESULTS:
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(d181/180) content was lower in LKO mice, which may explain the effect on insulin sensitivity. Ceramide(d181/180) 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(d181/180) 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 C180-ceramide is a potent regulator of hepatic insulin signaling linked to Pnpla3-mediated NAFLD.
Texto completo:
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Bases de datos:
MEDLINE
Asunto principal:
Resistencia a la Insulina
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Ceramidas
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Elongasas de Ácidos Grasos
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Hígado
Tipo de estudio:
Diagnostic_studies
Límite:
Animals
Idioma:
En
Revista:
Hepatology
Año:
2020
Tipo del documento:
Article
País de afiliación:
Japón