Effects of omega-3 fatty acids on fatty liver and insulin sensitivity.

Background of the study:

Hepatic steatosis is characterized by excessive triglyceride
accumulation in the liver which is caused by either excessive import,
diminished export and/or impaired beta-oxidation of fatty acids. Without
treatment, simple steatosis (non-alcoholic fatty liver disease, NAFLD) may
progress to an inflammatory state (non-alcoholic steatohepatitis, NASH) and
ultimately fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The
prevalence of NAFLD in industrialized populations ranges from 20-40%. NAFLD
is directly linked to obesity/the metabolic syndrome and with the epidemic
growth of obesity, a higher incidence of NAFLD is expected.
Weight loss is the most effective treatment strategy for hepatic steatosis.
Permanent weight loss in morbidly obese subjects can only be reached by
bariatric surgery. However, enlarged steatotic livers may complicate surgery
as in case of laparoscopic gastric bypass surgery it diminishes technical
maneuverability in the gastroesophageal area. In addition, steatotic livers
seem to be more vulnerable to complications caused by direct liver tissue
damage when the liver is mobilized or retracted during operation. Therefore
it may be of clinical benefit to reduce the degree of hepatic steatosis. In
a rat model of hepatic steatosis, we recently showed that supplementation of
omega-3 fatty acids significantly reduced TG accumulation in the liver
(Marsman et al, submitted). Fatty acids are activators of some nuclear
receptors involved in beta-oxidation, but until now it is not completely
unraveled whether and how omega-3 fatty acid supplementation affects hepatic
steatosis in humans.



Objective of the study:

The aim of this study is to evaluate the effect of supplementation
of a high oral dose of omega-3 fatty acids on hepatic steatosis and glucose
metabolism in morbidly obese patients undergoing laparoscopic Roux-Y gastric
bypass surgery (LRYGBP).



Study design:

Randomized controlled intervention study.



Study population:

Morbidly obese subjects scheduled for bariatric surgery, 18-65 years
old.



Intervention:

Eucaloric diet with high dose omega-3 fatty acids (SupportanR) vs
eucaloric diet without omega-3 fatty acids (FresubinR) 4 weeks prior to
laparoscopic Roux-Y gastic bypass surgery.



Primary study parameters/outcome of the study:

1. To assess the effects of omega-3 fatty acids on hepatic steatosis;

2. To assess the effects of omega-3 fatty acids on hepatic and peripheral
insulin resistance.



Secundary study parameters/outcome of the study:

1. Liver volume;

2. Fatty acids in the basal state and during hyperinsulinemia;

3. Plasma lipid profile;

4. Hepatic lipid profile;

5. Resting energy expenditure (REE);

6. Differences in expression profiles in liver tissue;

7. Histological classification of hepatic steatosis;

8. Changes in circulating inflammatory proteins.



Nature and extent of the burden and risks associated with participation,
benefit and group relatedness:

Biometric data such as waist circumference, BMI and blood pressure
will be measured. During surgery biopsies will be taken from visceral and
abdominal subcutaneous adipose tissue and the liver. The risks of bleeding
from the biopsy sites during the bariatric surgery procedure are very small
because the biopsy sites are completely visible to the surgeon and local
hemostasis will be checked. Subjects will visit the research unit weekly
during the study; total visit time will be about 34 hours. In addition an
MRS of the liver will be performed to quantify liver fat content. The
MRS-scan requires lying still as possible for 45 minutes. Subjects will
undergo a 2-step hyperinsulinemic euglycemic clamp using stable isotopes
before and after the diet period to study glucose metabolism. For the
administration of the stable isotope, glucose and insulin and for blood
sampling, intravenous canules will be inserted in the left and right
antecubital vein. Stable isotopes are not harmful and hypoglycaemia will not
occur because glucose is monitored every 5 minutes. Total clamping time on
one day will be 7 hours.

High dose of oral administration of omega-3 fatty acids ameliorates hepatic steatosis and insulin sensitivity in morbidly obese patients undergoing LRYGBP.

1. MRS liver + clamp pre-diet and post-diet;

2. Liverbiopsy post-diet during operation.

Eucaloric diet with high dose omega-3 fatty acids (Supportan®) vs. eucaloric diet without omega-3 fatty acids (Fresubin®) 4 weeks prior to laparoscopic Roux-Y gastic bypass surgery.