Hepatocyte ELOVL Fatty Acid Elongase 6 Determines Ceramide Acyl-Chain Length and Hepatic Insulin Sensitivity in Mice

Hepatology. 2020 May;71(5):1609-1625. doi: 10.1002/hep.30953. Epub 2020 Feb 7.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ceramides / chemistry
  • Ceramides / metabolism*
  • Dietary Sucrose / administration & dosage
  • Down-Regulation
  • Fatty Acid Elongases / genetics
  • Fatty Acid Elongases / physiology*
  • Insulin Resistance / genetics*
  • Liver / enzymology*
  • Mice
  • Mice, Knockout
  • Non-alcoholic Fatty Liver Disease / genetics
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Phospholipases A2, Calcium-Independent / metabolism
  • Protein Phosphatase 2 / metabolism
  • Sphingosine N-Acyltransferase / metabolism


  • Ceramides
  • Dietary Sucrose
  • Elovl6 protein, mouse
  • Fatty Acid Elongases
  • CERS4 protein, mouse
  • Sphingosine N-Acyltransferase
  • PNPLA3 protein, mouse
  • Phospholipases A2, Calcium-Independent
  • Protein Phosphatase 2