studies

1274A AASLD ABSTRACTS HEPATOLOGY, October, 2015
2187
Liver Fat and Inflammation Are Associated with Circulating
PCSK9 Levels
Paola Dongiovanni 1 , Massimiliano Ruscica 2 , Nicola Ferri 2 , Claudia
Lanti 2 , Raffaela Rametta 1 , Anna Ludovica Fracanzani 1 , Paolo
Magni 2 , Silvia Fargion 1 , Luca Valenti 1 ; 1 Internal Medicine, University
of Milano, Fondazione IRCCS Ca Granda, Milano, Italy;
2 University of Milan, Milan, Italy
Background and aims: Hepatocellular fat accumulation defines
nonalcoholic fatty liver disease (NAFLD), also known as hepatic
steatosis. Lipids accumulation derives from dietary fatty acids,
increased peripheral lipolysis due to adipose tissue insulin resistance
and elevated hepatic de novo lipogenesis due to hyperinsulinemia.
Altered secretion of very low-density lipoproteins
(VLDL) and free cholesterol accumulation also mediate hepatocellular
damage. However, NAFLD also confers increased risk
of cardiovascular events independently of classic risk factors.
Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) is an
important player in lipoprotein metabolism. Cleaved PCSK9 is
secreted by hepatocytes with VLDL and circulate with lipoproteins.
Soluble PCSK9 inhibits the uptake of low-density lipoproteins
(LDL) by targeting LDL receptor (LDL-R) to degradation, and
loss-of-function variants are associated with reduced circulating
cholesterol and protection from cardiovascular disease. However,
it is not known whether hepatic fat content and inflammation
modify PCSK9 levels. Aim was to evaluate whether hepatic
fat content affect circulating PCSK9 levels in individuals, who
underwent liver biopsy for suspected nonalcoholic steatohepatitis
(NASH). Methods: We considered 203 patients of Italian
ancestry who underwent biopsy for suspected NASH (n=126
for persistently elevated serum ALT, n=77 for severe obesity).
Serum PCSK9 levels were measured using a commercial ELISA
kit (R&D Systems, Minneapolis, MN, USA). Results: In NAFLD
patients, at univariate analysis PCSK9 levels were significantly
associated with steatosis severity (estimate +0.14±0.05
log ng/mL; p=0.006), inflammation (estimate +0.15±0.06;
p=0.01), and fibrosis (estimate +0.13±0.04; p=0.001). At
multivariate analysis, PCSK9 serum levels were significantly
associated with steatosis grade (estimate +0.13±0.06 log ng/
mL; p=0.03), age (estimate +0.008±0.004; p=0.03), BMI
(estimate -0.016±0.006; p=0.01) independently of sex, and
liver disease severity. In a subset of 30 obese patients, there
was no significant association between circulating PCSK9 concentration
and hepatic mRNA levels. Conclusions: Modulation
of serum PCSK9 by post-transcriptional mechanisms might be
involved in mediating the susceptibility to dyslipidemia and atherosclerosis
progression in patients with NAFLD, with potential
therapeutic implications.
Disclosures:
The following authors have nothing to disclose: Paola Dongiovanni, Massimiliano
Ruscica, Nicola Ferri, Claudia Lanti, Raffaela Rametta, Anna Ludovica Fracanzani,
Paolo Magni, Silvia Fargion, Luca Valenti
2188
Increasing severity of NAFLD is associated with gut dysbiosis
and modification of the metabolic function of the
gut microbiota
Jerome Boursier 1,3 , Olaf Mueller 2 , Matthieu Barret 4 , Mariana V.
Machado 5 , Lionel Fizanne 3 , Cynthia D. Guy 6 , John F. Rawls 2 , Lawrence
David 2 , Gilles Hunault 3 , Frederic Oberti 1,3 , Paul Cales 1,3 ,
Anna Mae Diehl 5 ; 1 Hepato-Gastroenterology Department, University
Hospital, Angers, France; 2 Center for Genomics of Microbial
Systems, Duke University, Durham, NC; 3 Laboratoire HIFIH
EA3859, University, Angers, France; 4 UMR1345, INRA, Beaucouzé,
France; 5 Division of Gastroenterology, Duke University
Medical Center, Durham, NC; 6 Department of Pathology, Duke
University, Durham, NC
Background: Several animal studies have suggested the role of
gut microbiota in Non-Alcoholic Fatty Liver Disease (NAFLD).
However, data about gut dysbiosis in human NAFLD remains
scarce in the literature, especially studies including the whole
spectrum of NAFLD lesions. We aimed to evaluate the association
between gut dysbiosis and the severity of NAFLD,
i.e. Non-Alcoholic Steatohepatitis (NASH) and fibrosis, in a
well-characterized cohort of adult NAFLD. Methods: 57 patients
with biopsy-proven NAFLD were enrolled. The taxonomic composition
of gut microbiota was determined using 16S ribosomal
RNA sequencing of stool samples. Results: 30 patients
had F0/1 fibrosis stage at liver biopsy (10 with NASH), and
27 patients had significant F ≥2 fibrosis (25 with NASH).
Bacteroides were significantly increased in NASH and F ≥2
patients, whereas Prevotella were decreased. Ruminococcus
were significantly higher in F ≥2 patients. Multivariate analysis
including age, sex, metabolic syndrome, serum transaminases,
gammaGT, ultrasensitive CRP, and gut microbiota data showed
that Bacteroides abundance was independently associated
with NASH and Ruminococcus with F≥2 fibrosis. Stratification
according to the abundance of these 2 bacteria generated
3 patient subgroups with increasing severity of NAFLD
lesions (low NASH/low fibrosis, high NASH/low fibrosis, high
NASH/ high fibrosis). Patients with a metabolic syndrome had
more severe liver lesions and, in those patients, NAFLD severity
increased according to the 3 gut microbiota subgroups. Based
on predicted metagenomics profile, the severity of NAFLD was
associated with significant microbiota enrichment in KEGG
pathways involved in carbohydrate metabolism (starch and
sucrose metabolism, pentose phosphate pathway, pentose and
glucoronate interconversions, pyruvate metabolism, glyoxylate
and dicarboxylate metabolism), lipid metabolism (lipid biosynthesis
proteins, sphingolipid metabolism), and amino acid
metabolism (arginine and proline metabolism, cyanoamino
acid metabolism). Conclusion: NAFLD severity associates with
gut dysbiosis and altered metabolic functions of the gut microbiota.
Bacteroides is an independent predictor for NASH and
Ruminococcus for fibrosis. Thus, gut microbiota analysis adds
information to classical predictors of NAFLD severity and suggests
novel metabolic targets for pre/pro-biotic therapies.
Disclosures:
Frederic Oberti - Speaking and Teaching: LFB, gore
Paul Cales - Consulting: BioLiveScale
The following authors have nothing to disclose: Jerome Boursier, Olaf Mueller,
Matthieu Barret, Mariana V. Machado, Lionel Fizanne, Cynthia D. Guy, John F.
Rawls, Lawrence David, Gilles Hunault, Anna Mae Diehl