Loss of hepatic SMLR1 causes hepatosteatosis and protects against atherosclerosis due to decreased hepatic VLDL secretion - Nantes Université Access content directly
Journal Articles Hepatology Year : 2022

Loss of hepatic SMLR1 causes hepatosteatosis and protects against atherosclerosis due to decreased hepatic VLDL secretion

Willemien van Zwol
  • Function : Author
Justina Wolters
  • Function : Author
Marieke Smit
  • Function : Author
Vincent Bloks
  • Function : Author
Niels Kloosterhuis
  • Function : Author
Nicolette Huijkman
  • Function : Author
Mirjam Koster
  • Function : Author
Umesh Tharehalli
  • Function : Author
Simon de Neck
  • Function : Author
Colin Bournez
  • Function : Author
Marceline Fuh
  • Function : Author
Jeroen Kuipers
  • Function : Author
Sujith Rajan
  • Function : Author
Alain de Bruin
  • Function : Author
Henry Ginsberg
  • Function : Author
Gerard van Westen
  • Function : Author
M. Mahmood Hussain
  • Function : Author
Ludger Scheja
  • Function : Author
Joerg Heeren
  • Function : Author
Philip Zimmerman
  • Function : Author
Bart van de Sluis
  • Function : Author
Jan Albert Kuivenhoven
  • Function : Author

Abstract

Hypobetalipoproteinemia is characterized by LDL-cholesterol and apolipoprotein B (apoB) plasma levels below the fifth percentile for age and sex. Familial hypobetalipoproteinemia (FHBL) is mostly caused by premature termination codons in the APOB gene, a condition associated with fatty liver and steatohepatitis. Nevertheless, many families with a FHBL phenotype carry APOB missense variants of uncertain significance (VUS). We here aimed to develop a proof-of-principle experiment to assess the pathogenicity of VUS using the genome editing of human liver cells. We identified a novel heterozygous APOB-VUS (p.Leu351Arg), in a FHBL family. We generated APOB knock-out (KO) and APOB-p.Leu351Arg knock-in Huh7 cells using CRISPR-Cas9 technology and studied the APOB expression, synthesis and secretion by digital droplet PCR and ELISA quantification. The APOB expression was decreased by 70% in the heterozygous APOB-KO cells and almost abolished in the homozygous-KO cells, with a consistent decrease in apoB production and secretion. The APOB-p.Leu351Arg homozygous cells presented with a 40% decreased APOB expression and undetectable apoB levels in cellular extracts and supernatant. Thus, the p.Leu351Arg affected the apoB secretion, which led us to classify this new variant as likely pathogenic and to set up a hepatic follow-up in this family. Therefore, the functional assessment of APOB-missense variants, using gene-editing technologies, will lead to improvements in the molecular diagnosis of FHBL and the personalized follow-up of these patients.

Dates and versions

hal-04060059 , version 1 (05-04-2023)

Identifiers

Cite

Willemien van Zwol, Antoine Rimbert, Justina Wolters, Marieke Smit, Vincent Bloks, et al.. Loss of hepatic SMLR1 causes hepatosteatosis and protects against atherosclerosis due to decreased hepatic VLDL secretion. Hepatology, 2022, 23 (8), pp.n/a-n/a. ⟨10.1002/hep.32709⟩. ⟨hal-04060059⟩
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