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 6

Reduced TG and apoB100 secretion from livers and isolated hepatocytes of A-CKO mice.

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Reduced TG and apoB100 secretion from livers and isolated hepatocytes of...
(A) Mice were injected with tyloxapol to block peripheral TG uptake, and plasma concentrations were measured at the indicated time points. Values represent the mean ± SEM (n = 4 mice per group). (B) TG secretion rates were calculated from the changes in plasma concentrations between 30 and 120 minutes in A. **P < 0.01, by Student’s t test. (C) Autoradiogram of SDS-polyacrylamide gel showing 35S-labeled plasma proteins collected 120 minutes after i.v. injection with 35S-methionine. Each lane shows plasma proteins from an individual mouse. Migrations of 35S-labeled apoB100 and apoB48 are indicated. (D) Bands corresponding to apoB100 and apoB48 in C were quantified by densitometry, (n = 4 mice per group). **P < 0.01, by Student’s t test. (E) Autoradiogram of SDS-polyacrylamide gel showing newly synthesized 35S-labeled proteins in cell lysates and media fractions of primary hepatocyte cultures. Migrations of 35S-labeled apoB100 and apoB48 are indicated (n = 3 different hepatocyte cultures from 1 mouse of each genotype). (F) Bands corresponding to apoB100 and apoB48 in E were quantified by densitometry. The left panel shows results from the media fraction, and the right panel shows results from cell lysate fraction. Results were normalized to the mean values from control samples and set to 100% (n = 3 different hepatocyte cultures from 1 mouse of each genotype). *P < 0.05, by Student’s t test. In B, D, and F, the values for individual mice are shown, with longer horizontal bars indicating the mean and vertical bars indicating the SEM. Mice used were 4 months old.