studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 667A
of melatonin regulated senescence and clock genes, including
EGR1, PAI-1, CCL2, CLOCK, PER1, BMAL1 and CRY1,
was significantly altered in chronic ethanol feeding mice livers
after anti-miR-34a Morpholino treatment relative to the controls.
Conclusion: The finding that melatonin plays a significant
role in the regulation of hepatocellular senescence phenotype
provides the basis for an exciting field in which the melatonin
related upstream enzyme (AANAT), the downstream miRNAs
(miR-34a) and clock circadian genes may be manipulated with
potential therapeutic benefits for alcoholic liver injury.
Disclosures:
The following authors have nothing to disclose: Jessica S. Garner, Yuyan Han,
Tiaohao Zhou, Kelly McDaniel, Ying Wan, Tami Annable, Nan Wu, Julie Venter,
Haibo Bai, Shannon S. Glaser, Heather L. Francis, Fanyin Meng, Gianfranco
Alpini
930
Hypoxia accelerates fatty acid uptake leading to
increased fat accumulation and inflammation in mice
and in cultured human hepatocyte-derived cells
Agueda Gonzalez-Rodriguez, Gloria Mateo, Ines Soro-Arnaiz,
Mar Torres-Capelli, Ainara Elorza, Julian Aragones, Carmelo
García-Monzón; Liver Research Unit, University Hospital Santa
Cristina, Madrid, Spain
Nonalcoholic fatty liver disease (NAFLD) is the most common
cause of chronic liver disease in Western countries. NAFLD is
strongly associated with overweight/obesity, insulin resistance,
type 2 diabetes (T2DM) and cardiovascular complications;
therefore, it is considered the hepatic component of the metabolic
syndrome. NAFLD is characterized by the progression
from a benign steatosis to more severe liver injuries directly
associated with lipotoxicity such as nonalcoholic steatohepatitis
(NASH), cirrhosis and hepatocellular carcinoma in 10% of
NAFLD patients. Recent evidence indicates that NAFLD severity
is affected by obstructive sleep apnoea syndrome (OSAS), a
recurrent upper-airway obstruction during sleep, leading to
periods of chronic intermittent hypoxia (CIH). In this regard,
dysregulation of the normal oxygen gradient in the liver that
promotes the stabilization of the hypoxia-inducible factors
(HIFs) can induce liver steatosis and inflammation. However,
the pathogenic mechanisms underlying the progression of
NAFLD to NASH in the context of CIH featuring OSAS are not
fully understood. As working hypothesis, the more pronounced
the CIH is, the more pronounced the progression to NASH and
fibrosis. AIM: The purpose of this study was focused on the
molecular mechanisms linking hypoxia to NAFLD/NASH setup.
METHODS: HIF system, CD36 content and liver damage markers
were analyzed in livers from conditional Von Hippel-Lindau
knockout (VHL-KO) mice, which display an overexpression of
HIFs after VHL gene deletion induced by tamoxifen, and in
HepG2 human hepatocytes loaded with palmitic acid submitted
to an hypoxic environment (1% O 2
). RESULTS: As expected,
HIF1 and HIF2 were overexpressed in livers from VHL-KO mice
compared to control mice. Remarkably, hepatic features of
NAFLD and NASH were found in livers from VHL-KO mice
together with increased lipid content. Accordingly, CD36 levels
were upregulated in these mice after VHL deletion. In human
hepatic cells, HIFs were stabilized under hypoxic conditions.
Interestingly, hypoxia itself enhanced fatty acid uptake monitored
by Nile Red staining due to the increase of CD36 translocation
to the plasma membrane. This event was parallel to
an increase of inflammatory markers. Noteworthy, palmitic-induced
lipotoxicity was more pronounced under hypoxic conditions.
CONCLUSIONS: Hypoxia accelerates fatty acid uptake,
largely due to CD36 translocation to the plasma membrane of
hepatocytes, leading to increased fat accumulation and inflammation
in mice and in cultured human hepatocyte-derived cells.
These results suggest that hypoxia could have a key pathogenic
role in the progression of NAFLD to NASH.
Disclosures:
The following authors have nothing to disclose: Agueda Gonzalez-Rodriguez,
Gloria Mateo, Ines Soro-Arnaiz, Mar Torres-Capelli, Ainara Elorza, Julian Aragones,
Carmelo García-Monzón
931
Predicted prevalence of NAFLD and NASH in a large
population using non-invasive multiparametric MRI
Catherine Kelly, Rajarshi Banerjee; Perspectum Diagnostics Ltd,
Oxford, United Kingdom
Aim: To determine the suitability of multiparametric MRI of
the liver for the assessment of NAFLD in large populations.
Methods: 1000 people, aged 40-69, were recruited from the
electoral register for multiparametric MRI, according to the
LiverMultiScan protocol. Liver disease status was unknown.
Estimates of liver fat fraction (PDFF %) and fibroinflammatory
disease (LIF score) were calculated using LiverMultiScan
software. Population statistics were compared to those in a
previously-reported cohort (Banerjee et al. 2014) with biopsy-proven
NASH (NAS ≥ 5). Results: In the unselected population
sample, 19.4% had steatosis (>5% PDFF), in agreement
with UK population estimates (Preiss & Sattar, 2008). In the reference
NASH cohort, 100% had steatosis (mean PDFF 29.6%).
The mean LIF score in the NASH cohort was 2.85 (s.d. 0.75).
A LIF score > 2 is associated with a higher likelihood of liver-related
clinical events (Pavlides, et al., 2014). In the unselected
group, LIF ranged from 0 to 3.2 with a mean of 0.89, (s.d.
0.3). In a plot of LIF vs PDFF, the NASH cohort can be used
to define the upper right quadrant (PDFF > 5% and LIF > 1.1).
Approximately 4% of the unselected cohort occupy the NASH
quadrant, in agreement with previous estimates of NASH prevalence
(Vernon et al. 2011). 9 of these individuals had LIF > 2.
Conclusion: Estimates of steatosis and NASH in an unselected
population agree with previous prevalence studies, suggesting
that multiparametric MRI is a promising technique for the
assessment of NAFLD. These findings encourage the use of this
methodology in other population studies, including screening.