The amounts of lipids within the western style diet have increased massively within the last decades. Considering this fact, it has become more and more relevant to deal with such diseases that are demonstrably associated with the phenomenon. In particular, the increasing incidences of gastrointestinal pathogeneses such as colorectal cancer or the chronic inflammatory bowel diseases seem to be functionally linked to the altered fatty acid uptake. The intestine is the central organ of the lipid resorption and therefore it is essential to understand the mechanisms involved within the metabolism of these nutrients. Here, the initial step is the activation of the long chain fatty acids to acyl-CoA thioester. This reaction is catalyzed by a group of enzymes called the long chain acyl-CoA synthetases (ACSLs). Today there are five different isoforms of ACSL described within the human and rodent organism of which the ACSL5 dominates the intestinal mucosa and has unique localization on the outer mitochondrial membrane. Within the enterocyte, there also exists some evidence that this enzyme is involved in the regulation of the cell’s maturation as well as survival by sensitizing it to apoptosis. But after all, the available information about the intestinal ACSL5 is still meager. Thus, the principle goal of the current studies was the characterization of the ACSL5 within the human digestive tract. By using an in vitro model based on cell culture experiments it was supposed to gain further information about the ACSL5’s position in the enterozytic lipid metabolism and the putative interactions with other functional signal pathways. The lipid metabolism was inhibited at different positions: Orlistat blocked the endogenous fatty acid synthesis while Etomoxir stopped the fatty acid transport into the mitochondrion as compartment of the beta-oxidation. After treatment the cells’ ACSL5 was examined by several methods including qRT-PCR, Western blotting and enzyme activity assay. ACSL5 was up regulated on the mRNA- as well as the proteomic level. Furthermore the enzymatic activity increases, too. Beyond this, molecular genetic examinations reveal possible ACSL5 dependent regulated genes like the free-fatty acid-receptors 2 and 3 (FFAR2 and 3) or Mortalin (HSPA9), a member of the so-called heat shock protein 70 (Hsp70) family. This supposes on the one hand a predominant catabolic function of ACSL5 within the enterocyte. On the other hand the association with the mitochondrial Mortalin demonstrates a potential clue to cellular stress caused by ACLS5 activity. Regarding putative functional connections between ACSL5 and apoptosis, it came out that proapoptotic genes such as Caspase 8 and Bid were also increased under treatment. These results show that ACSL5’s induction might stimulates the cell towards apoptosis. Microscopical observation supported this presumption: High levels of Orlistat led to a disruption in cell growth. Transmission electron microscopy however could not show an ACSL5 associated alteration. In summary, these experimental data evidence a much more complex role of the enterozytic ACSL5 than expected. It is not just the key player within the lipid metabolism, but also seems to be involved in other functional pathways which regulate the cell’s homeostasis. First hints show a putative influence on the apoptosis and other ACSL5-related regulated molecules
