Nuclear envelope–localized torsinA-LAP1 complex regulates hepatic VLDL secretion and steatosis
Ji-Yeon Shin, … , Henry N. Ginsberg, Howard J. Worman
Ji-Yeon Shin, … , Henry N. Ginsberg, Howard J. Worman
Published August 13, 2019
Citation Information: J Clin Invest. 2019;129(11):4885-4900. https://doi.org/10.1172/JCI129769.
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Research Article Cell biology Metabolism

Nuclear envelope–localized torsinA-LAP1 complex regulates hepatic VLDL secretion and steatosis

Abstract

Deciphering novel pathways that regulate liver lipid content has profound implications for understanding the pathophysiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Recent evidence suggests that the nuclear envelope is a site of regulation of lipid metabolism, but there is limited appreciation of the responsible mechanisms and molecular components within this organelle. We showed that conditional hepatocyte deletion of the inner nuclear membrane protein lamina-associated polypeptide 1 (LAP1) causes defective VLDL secretion and steatosis, including intranuclear lipid accumulation. LAP1 binds to and activates torsinA, an AAA+ ATPase that resides in the perinuclear space and continuous main ER. Deletion of torsinA from mouse hepatocytes caused even greater reductions in VLDL secretion and profound steatosis. Mice from both of the mutant lines studied developed hepatic steatosis and subsequent steatohepatitis on a regular chow diet in the absence of whole-body insulin resistance or obesity. Our results establish an essential role for the nuclear envelope–localized torsinA-LAP1 complex in hepatic VLDL secretion and suggest that the torsinA pathway participates in the pathophysiology of NAFLD.

Authors

Ji-Yeon Shin, Antonio Hernandez-Ono, Tatyana Fedotova, Cecilia Östlund, Michael J. Lee, Sarah B. Gibeley, Chun-Chi Liang, William T. Dauer, Henry N. Ginsberg, Howard J. Worman

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Figure 2

De novo lipogenesis, fatty acid oxidation, and plasma free fatty acids in livers of L-CKO mice.

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De novo lipogenesis, fatty acid oxidation, and plasma free fatty acids i...
(A) De novo lipogenesis in the livers of control and L-CKO mice. Newly synthesized hepatic lipids were measured by incorporation of 3H into fatty acids (FAs) 1 hour after i.p. injection with 3H2O (n = 6 mice per genotype). P = NS, by Student’s t test. (B) Oxidation of fatty acids in hepatocytes isolated from control and L-CKO mice. Oxidative products of 14C-oleic acid (14CO2 and 14C-labeled acid-soluble metabolites) were measured and normalized to milligrams of cellular protein (n = 3 mice per genotype). P = NS, by Student’s t test. (C) Free fatty acids (FFAs) were measured from snap-frozen plasma samples from control and L-CKO mice after a 4- to 5-hour fast. The values for individual mice are shown, with longer horizontal bars indicating the mean and vertical bars indicating the SEM. Mice used were 4–6 months of age.