Metabolic and signaling pathways in steatosis and steatohepatitis

Obesity is presently an increasing problem. At this moment, almost half of the
European citizens are overweight and a third of these people are obese. This
increase in the number of overweight people is mainly due to the current
sedentary lifestyle and the changes in food consumption. If more energy is
taken up by the body than is consumed over a long period, the excess of energy
is stored in the adipose tissue, and, to a lesser extent, in liver and muscle
tissue. Once this fat is stored, it is not easily mobilized again. Because of
this, obesity is defined as a chronic condition. Furthermore, obesity is
associated with cardiovascular diseases, diabetes, etc.
The increased fat content in the liver and the muscle impairs mitochondrial
function and, hence, the energy supply of these organs. Fat accumulation in the
liver leads also without alcohol abuse to non-alcoholic fatty liver disease
(NAFLD). NAFLD can be divided into different stages: fat accumulation
(steatosis), fat accumulation and inflammation (steatohepatitis), formation of
scar tissue (cirrhosis), and hepatocellular carcinoma. These different stages
of NAFLD are characterized by a different degree of fat accumulation, cell
death, inflammation, and scar tissue. We hypothesize that the disturbed energy
production is caused by the inhibition of aconitase, which is an enzyme
normally involved in energy production. As a consequence of the inhibition of
aconitase, fat accumulation occurs.

In this study we want to make an inventory of the metabolic and inflammatory
pathways which are significantly affected by the development of steatosis and
steatohepatitis in human liver. We also want to relate these mechanisms with
the different stages of NAFLD.

In this human study, a bank of liver biopsies of the entire spectrum of NAFLD,
ranging from healthy to cirrhosis, will be generated. We will be collecting
approximately 80 liver biopsies. In this manner we hope to be able to include
at least 10 samples of each of the different stages of NAFLD. These liver
biopsies will be acquired from partial hepatectomies that are performed to
remove metastases of colon carcinoma and from liver biopsies of patients
undergoing bariatric surgery for the treatment of morbid obesity. To classify
the liver biopsies in one of the NAFLD stages the grading system developed by
Kleiner et al. (Hepatology, 2005) will be used. The obtained liver biopsies
will be subjected to micro-array analysis to identify the affected metabolic
and inflammatory pathways in the development of steatosis and steatohepatitis.
In this manner we want to correlate the staging system with these affected
metabolic and inflammatory pathways.

The collection of liver biopsies for this study will be without any additional
risks for the patients. In the patients with colon metastasis in the liver a
liver specimen is taken as treatment of the disease. In this study we will use
a liver biopsy from this liver specimen, and as a consequence no additional
specimens need to be taken from the liver for this study. In the patients
undergoing bariatric surgery a liver biopsy is taken as a standard for
research. It is shown in previous studies that taking liver biopsies is without
any risk for the patient (MEC 02-045.3).