title: Liver fat accumulation is associated with circulating PCSK9.
abstract: Nonalcoholic fatty liver disease (NAFLD) associates with cardiovascular disease independently of classic risk factors. Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) is secreted by hepatocytes and inhibits the uptake of low-density lipoproteins by targeting the receptor for degradation, and possibly lipogenesis. PCSK9 loss-of-function mutations and anti-PCKS9 drugs reduce LDL-cholesterol.
  
  
  
  To evaluate whether hepatic fat content is associated with circulating PCSK9.
  
  
  
  In 201 consecutive patients biopsied for suspected nonalcoholic steatohepatitis, liver damage was quantified by NAFLD activity score, circulating PCSK9 by ELISA, and hepatic mRNA by qRT-PCR in a subset (n = 76).
  
  
  
  Circulating PCSK9 was associated with steatosis grade (p = 0.0011), necroinflammation (p < 0.001), ballooning (p = 0.005), and fibrosis stage (p = 0.001). At multivariate analysis, PCSK9 was associated with steatosis grade (p = 0.012), older age and lower BMI, independently of sex, hyperglycemia, and fibrosis/inflammation. Circulating PCSK9 was associated with hepatic expression of SREBP-1c (p = 0.0002) and FAS (p = 0.03). PCSK9 mRNA levels were also correlated with steatosis severity (p = 0.04) and hepatic APOB (p < 0.001), SREBP-1c (p = 0.047) and FAS expression (p = 0.001).
  
  
  
  Circulating PCSK9 increases with hepatic fat accumulation and correlates with the severity of steatosis, independently of metabolic confounders and liver damage. Modulation of PCSK9 synthesis and release might be involved in NAFLD pathogenesis. Key Messages Circulating PCSK9 levels increase with hepatic fat accumulation. Circulating PCSK9 levels are associated with increased de novo lipogenesis. Hepatic PCSK9 expression is associated with steatosis severity and activation of lipogenesis.
authors.affiliation: a Department of Pharmacological and Biomolecular Sciences , Università Degli Studi Di Milano , Milano , Italy ;
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Ruscica
authors.affiliation: b Department of Pharmaceutical and Pharmacological Sciences , Università di Padova , Padova , Italy ;
authors.forename: Nicola
authors.initials: N
authors.lastname: Ferri
authors.affiliation: a Department of Pharmacological and Biomolecular Sciences , Università Degli Studi Di Milano , Milano , Italy ;
authors.forename: Chiara
authors.initials: C
authors.lastname: Macchi
authors.affiliation: c Department of Pathophysiology and Transplantation , Università Degli Studi Di Milano , Milano , Italy ;
authors.forename: Marica
authors.initials: M
authors.lastname: Meroni
authors.affiliation: d Internal Medicine and Metabolic Diseases , Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milano , Italy ;
authors.forename: Claudia
authors.initials: C
authors.lastname: Lanti
authors.affiliation: a Department of Pharmacological and Biomolecular Sciences , Università Degli Studi Di Milano , Milano , Italy ;
authors.forename: Chiara
authors.initials: C
authors.lastname: Ricci
authors.affiliation: e Department of Pathology , Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milano , Italy ;
authors.forename: Marco
authors.initials: M
authors.lastname: Maggioni
authors.affiliation: c Department of Pathophysiology and Transplantation , Università Degli Studi Di Milano , Milano , Italy ;|d Internal Medicine and Metabolic Diseases , Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milano , Italy ;
authors.forename: Anna Ludovica
authors.initials: AL
authors.lastname: Fracanzani
authors.affiliation: f Department of Surgery , Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milano , Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Badiali
authors.affiliation: c Department of Pathophysiology and Transplantation , Università Degli Studi Di Milano , Milano , Italy ;|d Internal Medicine and Metabolic Diseases , Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milano , Italy ;
authors.forename: Silvia
authors.initials: S
authors.lastname: Fargion
authors.affiliation: a Department of Pharmacological and Biomolecular Sciences , Università Degli Studi Di Milano , Milano , Italy ;
authors.forename: Paolo
authors.initials: P
authors.lastname: Magni
authors.affiliation: c Department of Pathophysiology and Transplantation , Università Degli Studi Di Milano , Milano , Italy ;|d Internal Medicine and Metabolic Diseases , Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milano , Italy ;
authors.forename: Luca
authors.initials: L
authors.lastname: Valenti
authors.affiliation: d Internal Medicine and Metabolic Diseases , Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milano , Italy ;
authors.forename: Paola
authors.initials: P
authors.lastname: Dongiovanni
mesh_terms: D000328:Adult; D053299:Apolipoprotein B-100 / Q000378:metabolism; D005260:Female; D006801:Humans; D050155:Lipogenesis; D008077:Lipoproteins, LDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism*; D011379:Prognosis; D000071449:Proprotein Convertase 9 / Q000097:blood* / Q000235:genetics*; D012307:Risk Factors; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: C569471:APOB protein, human; D053299:Apolipoprotein B-100; C491901:FAS protein, human; D008077:Lipoproteins, LDL; D051780:Sterol Regulatory Element Binding Protein 1; D019014:fas Receptor; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9
keywords: Lipids; NAFLD; lipoproteins/metabolism; lipoproteins/receptors; liver