Project details


Non-alcoholic fatty liver disease (NAFLD): pathogenesis and interventions

inflammation fatty liver disease lipotoxicity

prof.dr. H. Moshage

Nature of the research:
Experimental research on non-alcoholic fatty liver disease (liver cell isolation and culture; lipotoxicity; signal transduction)

Fields of study:
cell biology gastroenterology

Background / introduction
Non-alcoholic fatty liver disease (NAFLD) poses an increasing threat globally and is believed to be the most frequent liver disease leading to mortality and the most frequent cause for liver transplantation in the near future. NAFLD comprises a spectrum of clinicopathological phenomena, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) and eventually may develop into cirrhosis and hepatocellular carcinoma. The current prevalence of NAFLD is estimated to be around 25% globally. The prevalence of NAFLD in obese or type 2 diabetes mellitus (T2DM) patients is even higher: the global prevalence of NAFLD among patients with T2DM has been reported to be 55.5% and among morbidly obese subjects who underwent weight reduction surgery more than 95%
Research question / problem definition
Non-alcoholic fatty liver disease (NAFLD) comprises the spectrum of liver diseases that is the result of excessive lipid accumulation and disturbed lipid metabolism in the liver. This spectrum ranges from simple hepatic steatosis, to (chronic) inflammation (non-alcoholic steatohepatitis; NASH) and eventually fibrosis and cirrosis.

In our research on NAFLD we focus on the mechanisms and manipulation of cell death, inflammation and fibrogenesis. We explore the mechanisms of lipotoxicity, with special emphasis on free fatty acid-induced cell death, endoplasmic reticulum (ER) stress and mitochondrial dysfunction.
Within this research line, the following sub-lines are identified:

Mechanisms of free fatty acid-induced lipotoxicity:
Increased plasma levels of free fatty acids and lipid accumulation in hepatocytes are hallmarks of NAFLD. The excessive accumulation of lipids in hepatocytes leads to cell death. We aim to elucidate the mechanisms of FFA-induced lipotoxicity in hepatocytes, focusing on intracellular FFA metabolism (FFA storage in triglycerides, β-oxidation, saturated vs unsaturated FFAs).

Extracellular vesicle-mediated intercellular communication in NAFLD:
Extracellular vesicles (EVs) are small, membrane-bound vesicles released from a wide variety of cells, including liver cells. They play an important role in intercellular communication. The cargo of EVs is diverse and includes RNAs (miRNAs), lipids and proteins. EVs released from steatotic hepatocytes have pro-inflammatory effects on Kupffer cells, the resident macrophages of the liver) and pro-fibrotic effects on hepatic stellate cells (liver-specific, matrix-producing cells of the liver).
In addition, liver sinusoidal endothelial cells (LSECs) play an important role in the initiation of NAFLD via effects on stellate cells and (possibly) Kupffer cells.

Drug-induced liver injury in NAFLD:
In this subline we aim to elucidate the role of EVs in intercellular communication, focusing on hepatocyte-Kupffer cell; hepatocyte-stellate cell; LSEC-stellate cell, LSEC-Kupffer cell and stellate cell-Kupffer cell communication.

Drug-induced liver injury in NAFLD:
The expresssion of drug-metabolizing enzymes, notably cytochrome P450 (CYP) isozymes, is changed in steatotic hepatocytes, compared to normal hepatocytes. This will have consequences for the metabolism, activity and toxicity of many drugs. In this subline, we investigate the consequences of steatosis for drug metabolism and drug toxicity in hepatocytes.
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