Dynamic regulation of hepatic lipid metabolism by torsinA and its activators
Antonio Hernandez-Ono, Yi Peng Zhao, John W. Murray, Cecilia Östlund, Michael J. Lee, Angsi Shi, William T. Dauer, Howard J. Worman, Henry N. Ginsberg, Ji-Yeon Shin
Antonio Hernandez-Ono, Yi Peng Zhao, John W. Murray, Cecilia Östlund, Michael J. Lee, Angsi Shi, William T. Dauer, Howard J. Worman, Henry N. Ginsberg, Ji-Yeon Shin
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Research Article Hepatology Metabolism

Dynamic regulation of hepatic lipid metabolism by torsinA and its activators

Abstract

Depletion of torsinA from hepatocytes leads to reduced liver triglyceride secretion and marked hepatic steatosis. TorsinA is an atypical ATPase that lacks intrinsic activity unless it is bound to its activator, lamina-associated polypeptide 1 (LAP1) or luminal domain–like LAP1 (LULL1). We previously demonstrated that depletion of LAP1 from hepatocytes has more modest effects on liver triglyceride secretion and steatosis development than depletion of torsinA. We now show that depletion of LULL1 alone does not significantly decrease triglyceride secretion or cause steatosis. However, simultaneous depletion of both LAP1 and LULL1 leads to defective triglyceride secretion and marked steatosis similar to that observed with depletion of torsinA. Depletion of both LAP1 and torsinA from hepatocytes generated phenotypes similar to those observed with only torsinA depletion, implying that the 2 proteins act in the same pathway in liver lipid metabolism. Our results demonstrate that torsinA and its activators dynamically regulate hepatic lipid metabolism.

Authors

Antonio Hernandez-Ono, Yi Peng Zhao, John W. Murray, Cecilia Östlund, Michael J. Lee, Angsi Shi, William T. Dauer, Howard J. Worman, Henry N. Ginsberg, Ji-Yeon Shin

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Figure 1

Mice with depletion of LULL1 from hepatocytes show no overt liver abnormalities.

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Mice with depletion of LULL1 from hepatocytes show no overt liver abnorm...
(A) Representative photographs of livers from 4-month-old control (LUL-flox) and LUL-CKO mice fed a chow diet. Scale bars: 1 cm. (B) Liver-to-body mass ratios of LUL-flox (n = 10) and LUL-CKO mice (n = 12). (C) IB of liver lysates from LUL-flox and LUL-CKO mice probed with Abs against LULL1 and β-actin. Each lane is a sample from a different mouse. The anti-LULL1 Ab detects 2 closely migrating bands (14). (D) Representative light photomicrographs of liver sections from chow-fed mice stained with H&E or Oil Red O. Scale bars: 50 μm. (E) Liver TG content of LUL-flox (n = 10) and LUL-CKO (n = 12) mice. Mice were fasted for 4–5 hours before collecting livers to measure TG content. (F) Plasma TG concentration versus time after injection of tyloxapol to block peripheral uptake in LUL-CKO (n = 12) and LUL-flox (n = 10) mice. (G) TG secretion rates calculated from the changes in plasma concentrations between 30 and 120 minutes in F. (H) Autoradiogram of SDS-polyacrylamide gel showing 35S-labeled plasma proteins collected 120 minutes after injection with 35S-methionine and tyloxapol. Each lane shows proteins from an individual mouse. Migrations of 35S-methionine–labeled apoB100 and apoB48 are indicated (n = 5 mice per group). (I) Bands corresponding to apoB100 and apoB48 shown in panel F were quantified by densitometry and shown as a percentage of the value from the LUL-flox group (n = 5 mice per group). In panels B, E–G, and I, values are mean ± SEM, with each circle or triangle representing the value from an individual mouse. NS, not significant by unpaired, 2-tailed Student’s t test.