Ablation of Bscl2/Seipin in hepatocytes does not cause metabolic dysfunction in congenital generalised lipodystrophy

George D Mcilroy* (Corresponding Author), Sharon E Mitchell, Weiping Han, Mirela Delibegović, Justin J Rochford

*Corresponding author for this work

Research output: Contribution to journalArticle

4 Downloads (Pure)

Abstract

Mutations affecting the BSCL2 gene cause the most severe form of congenital generalised lipodystrophy (CGL). Affected individuals develop severe metabolic complications including diabetes and hepatic steatosis. Bscl2-deficient mice almost entirely reproduce the CGL phenotype. Adipose tissue-specific loss of Bscl2 is also sufficient to cause early-onset generalised lipodystrophy in mice. However, these mice do not show severe metabolic dysfunction, even when challenged with a high-fat diet. Germline Bscl2 loss in mice and BSCL2 disruption in humans causes severe hepatic steatosis and the encoded protein, seipin, has acknowledged roles in lipid accumulation. Given the critical role of the liver in glucose regulation, we speculated that intact hepatic Bscl2 expression may protect adipose tissue-specific Bscl2-deficient mice from metabolic disease. To investigate this, we generated a novel mouse model where Bscl2 has been deleted in both adipose tissue and hepatocytes simultaneously using an adeno-associated viral vector. Despite achieving efficient disruption of Bscl2 in the liver, hepatic lipid accumulation and metabolic homeostasis was unaffected in mice fed a high-fat diet for four weeks. We also investigated the consequences of BSCL2 ablation in the human hepatocyte HepG2 cell line using CRISPR/Cas9 genome editing. No significant increases in lipid accumulation were observed in BSCL2 knockout cell lines. Overall, we reveal that Bscl2/BSCL2 does not appear to play a cell autonomous role in the regulation of lipid accumulation in the liver. Loss of hepatic BSCL2 is therefore unlikely to contribute significantly to the development of hepatic steatosis or metabolic dysfunction in this form of CGL.

Original languageEnglish
Article numberdmm042655
Number of pages10
JournalDisease Models & Mechanisms
Volume13
Issue number1
Early online date17 Dec 2019
DOIs
Publication statusPublished - 17 Jan 2020

Keywords

  • Lipodystrophy
  • BSCL2CGL
  • Hepatocyte
  • AAV
  • CRISPR
  • BSCL2
  • CGL
  • INSULIN SENSITIVITY
  • SEIPIN
  • LIPOLYSIS
  • RESISTANCE
  • MICE
  • KNOCKOUT

Fingerprint Dive into the research topics of 'Ablation of Bscl2/Seipin in hepatocytes does not cause metabolic dysfunction in congenital generalised lipodystrophy'. Together they form a unique fingerprint.

Cite this