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 5

Hepatic steatosis without evidence of insulin resistance in male A-CKO mice fed a chow diet.

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Hepatic steatosis without evidence of insulin resistance in male A-CKO m...
(A) Photographs of livers from male control (Tor1afl/+) and A-CKO (AlbCre Tor1afl/–) mice fed a chow diet. Scale bar: 1 cm. (B) Representative light micrographs of H&E- and Oil Red O–stained liver sections from chow-fed mice. Scale bar: 50 μm. (C) Liver TG and cholesterol content. Mice were fasted for 4 to 5 hours before livers were collected (n = 4 mice per group). **P < 0.01 and ***P < 0.001, by Student’s t test. (D) Plasma TG and cholesterol concentrations (n = 4 mice per group). **P < 0.01, by Student’s t test. (E) Blood glucose concentrations versus time after injection of a glucose bolus into overnight-fasted mice (n = 5 mice per group). Results were not significantly different at any time point by ANOVA. (F) Serum insulin concentrations. Mice were fasted for 5 hours before plasma was collected (n = 3–5 mice per group). P = NS, by Student’s t test. (G) Electron micrographs of liver sections from 4-month-old control and A-CKO mice. Top panel shows low-magnification images of a single hepatocyte from control and A-CKO samples. The lower panel is a magnified image of the dashed-line square region in the upper panel. Scale bars: 10 μm (upper panel) and 500 nm (lower panel). N, nucleus. (H) Confocal micrographs of isolated hepatocytes. Lipids were stained with BODIPY (green) and nuclei with DAPI (blue). The right panel is a zoomed image of the dashed-line square region. Scale bars: 10 μm (zoom, 10 μm). In C, 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 4–6 months old.