title: Hepatic BSCL2 (Seipin) Deficiency Disrupts Lipid Droplet Homeostasis and Increases Lipid Metabolism via SCD1 Activity.
abstract: Berardinelli-Seip congenital lipodystrophy (BSCL) is an autosomal recessive disorder. The more severe form, designated BSCL2, arises due to mutations in the BSCL2 gene. Patients with BSCL2, as well as Bscl2-/-mice, have a near total absence of body fat, an organomegaly, and develop metabolic disorders including insulin resistance and hepatic steatosis. The function of the Seipin (BSCL2) protein remains poorly understood. Several lines of evidence have indicated that Seipin may have distinct functions in adipose versus non-adipose cells. Here we present evidence that BSCL2/Bscl2 plays a role in lipid droplet (LD) biogenesis and homeostasis in primary and cultured hepatocytes. Our results show that decreasing BSCL2/Bscl2 expression in hepatocytes increases the number and size of LD, as well as the expression of genes implicated in their formation and stability. We also show that knocking down SCD1 expression reverses the phenotype associated with Seipin deficiency. Interestingly, BSCL2 knockdown induces SCD1 expression and activity, potentially leading to increased basal phosphorylation of proteins involved in the insulin signaling cascade, as well as further increasing fatty acid uptake and de novo lipogenesis. In conclusion, our results suggest that a hepatic BSCL2/Bscl2 deficiency induces the increase and expansion of LD, potentially via increased SCD1 activity.
authors.affiliation: Département des sciences biologiques et centre de recherche BioMed, Université du Québec à Montréal, Case Postale 8888, Succursale Centre-ville, Montréal, QC, H3C 3P8, Canada.
authors.forename: Mohamed Amine
authors.initials: MA
authors.lastname: Lounis
authors.affiliation: Département des sciences biologiques et centre de recherche BioMed, Université du Québec à Montréal, Case Postale 8888, Succursale Centre-ville, Montréal, QC, H3C 3P8, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Lalonde
authors.affiliation: Département des sciences biologiques et centre de recherche BioMed, Université du Québec à Montréal, Case Postale 8888, Succursale Centre-ville, Montréal, QC, H3C 3P8, Canada.
authors.forename: Sabri Ahmed
authors.initials: SA
authors.lastname: Rial
authors.affiliation: Département des sciences biologiques et centre de recherche BioMed, Université du Québec à Montréal, Case Postale 8888, Succursale Centre-ville, Montréal, QC, H3C 3P8, Canada.
authors.forename: Karl-F
authors.initials: KF
authors.lastname: Bergeron
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada.
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Ralston
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada.
authors.forename: David M
authors.initials: DM
authors.lastname: Mutch
authors.affiliation: Département des sciences biologiques et centre de recherche BioMed, Université du Québec à Montréal, Case Postale 8888, Succursale Centre-ville, Montréal, QC, H3C 3P8, Canada. mounier.catherine@uqam.ca.
authors.forename: Catherine
authors.initials: C
authors.lastname: Mounier
mesh_terms: D000818:Animals; D044388:GTP-Binding Protein gamma Subunits / Q000172:deficiency*; D055879:Gene Knock-In Techniques; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000378:metabolism; D066292:Lipid Droplets / Q000378:metabolism*; D050356:Lipid Metabolism; D053141:Organelle Size; D010766:Phosphorylation; D051381:Rats; D013230:Stearoyl-CoA Desaturase / Q000235:genetics* / Q000378:metabolism
chemical_list: C432679:BSCL2 protein, human; D044388:GTP-Binding Protein gamma Subunits; D007328:Insulin; C523776:SCD1 protein, human; D013230:Stearoyl-CoA Desaturase
keywords: BSCL2; Fatty acid uptake; Insulin sensitivity; Lipid droplets; Lipogenesis; SCD1; Seipin