ACTA BIOLOGICA CRACOVIENSIA

NUTRITIONAL CAROTENOIDS AND THEIR IMPLICATION IN HUMAN HEALTH
Non-alcoholic fatty liver disease (NAFLD) is one of the most common
liver disorders worldwide. NAFLD ranges from hepatic
steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis.
The prevalence of NAFLD is associated with obesity and
insulin resistance (1). Recent evidence has shown that downstream
targets of retinoic acid play a pivotal role in the aetiology
of NAFLD and NASH, since transgenic mice expressing the
retinoic acid receptor-alpha dominant negative form developed
microvesicular steatosis and spotty focal necrosis (2).
Furthermore, beta-carotene 15,15'-monoxygenase (BCMO1),
responsible for the local de novo production of retinal, has shown
to be involved in the development of liver steatosis (3).
Since BCMO1 knockout (BCMO1 KO) animals develop liver
steatosis independently of the vitamin A status of the diet, we
wanted to investigate the mechanisms contributing to this effect
using a microarray approach. Here we describe that loss of
retinoid signalling contributes to the production of ROS and
increases portal tract inflammation. Microarray analysis indicated
that both oxidative stress (21% affected genes, Z-Score 2.6)
and inflammatory response (18.5% affected genes, Z-score 2.6)
pathways were significantly affected, but that fatty acid oxidation
and biosynthesis were not changed. Our results show that the
development of NAFLD in BCMO1 KO animals does not require
the progression from simple fatty liver to fibrosis (two hit hypothesis)
which indicates that a different mechanism is driving the
development of steatohepatitis in BCMO1 deficiency.
In addition, we screened biopsy proven NAFLD patients
(n=339) for their genetic variations in the BCMO1 gene.
Interestingly, carriers of 379V alleles have a higher overall risk of
developing NASH with OR of 1.85 (p