Expression of fatty acid synthase in nonalcoholic fatty liver disease - PubMed (original) (raw)
. 2010 Mar 25;3(5):505-14.
Affiliations
- PMID: 20606731
- PMCID: PMC2897101
Expression of fatty acid synthase in nonalcoholic fatty liver disease
Christoph Dorn et al. Int J Clin Exp Pathol. 2010.
Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation which starts with simple hepatic steatosis and may progress toward inflammation (nonalcoholic steatohepatitis [NASH]). Fatty acid synthase (FASN) catalyzes the last step in fatty acid biosynthesis, and thus, it is believed to be a major determinant of the maximal hepatic capacity to generate fatty acids by de novo lipogenesis. The aim of this study was to analyze the correlation between hepatic steatosis and inflammation with FASN expression. In vitro incubation of primary human hepatocytes with fatty acids dose-dependently induced cellular lipid-accumulation and FASN expression, while stimulation with TNF did not affect FASN levels. Further, hepatic FASN expression was significantly increased in vivo in a murine model of hepatic steatosis without significant inflammation but not in a murine NASH model as compared to control mice. Also, FASN expression was not increased in mice subjected to bile duct ligation, an experimental model characterized by severe hepatocellular damage and inflammation. Furthermore, FASN expression was analyzed in 102 human control or NAFLD livers applying tissue micro array technology and immunohistochemistry, and correlated significantly with the degree of hepatic steatosis, but not with inflammation or ballooning of hepatocytes. Quantification of FASN mRNA expression in human liver samples confirmed significantly higher FASN levels in hepatic steatosis but not in NASH, and expression of SREBP1, which is the main transcriptional regulator of FASN, paralleled FASN expression levels in human and experimental NAFLD. In conclusion, the transcriptional induction of FASN expression in hepatic steatosis is impaired in NASH, while hepatic inflammation in the absence of steatosis does not affect FASN expression, suggesting that FASN may serve as a new diagnostic marker or therapeutic target for the progression of NAFLD.
Keywords: Fatty acid synthase (FASN); Nonalcoholic fatty liver disease (NAFLD); SREBP1; expression; immunohistochemistry; nonalcoholic steatohepatitis (NASH).
Figures
Figure 1
FASN expression in an in vitro model of hepatocellular lipid accumulation. Primary human hepatocytes were incubated with 0.2 mM and 0.4 mM palmitate (Palm.) or TNF (10 ng/ml) for 24 h. (A) Colorimetric assessment of intracellular triglyceride content. (B,C) Analysis of FASN mRNA expression by quantitative PCR. (*p<0.05 compared to control (ctr.)).
Figure 2
Hepatic FASN expression in two murine models of NAFLD and in a model of hepatic injury and inflammation not related to NAFLD. Mice were fed either a high fat diet leading to hepatic steatosis or a NASH inducing diet for 12 weeks. Mice receiving standard chow served as control (ctr.). In a second experimental setting mice underwent bile duct ligated (BDL) for 3 weeks to induce liver injury and hepatic inflammation (without steatosis). Sham-operated mice served as control (sham). (A) HE-staining of liver tissue sections from mice fed either high fat (II), NASH inducing (III) or control diet (I). (magnification 100×) (B,C) Analysis of hepatic FASN, TNF and MCP-1 mRNA expression by quantitative PCR. (*p<0.05 compared to control).
Figure 3
FASN expression in liver tissues of patients with and without NAFLD. (A) FASN immunohistochemical staining of a tissue micro array comprising 106 non-tumorous hepatic tissue specimens with different degree of steatosis and inflammation. Representative pictures of a (I) healthy liver, weakly positive for FASN (arrow: the coarse brown material is lipofuscin), (II) steatotic liver without inflammation showing strong cytoplasmatic positivity for FASN, and (III) NASH liver, weakly positive for FASN (bold arrow: lobular inflammation; thin arrow: the coarse brown material is lipofuscin). Magnification 200× and 400× in the insert, respectively. (B) Comparison of FASN mRNA expression levels in liver samples with high or low FASN protein expression as assessed by semiquantitative evaluation of FASN immunohistochemistry (IH). (C) Analysis of FASN mRNA expression levels in normal (ctr.), steatotic and NASH human liver tissues by quantitative PCR. (*p<0.05 compared to control).
Figure 4
SREBP1 expression in in vitro and in vivo models of hepatic steatosis and human NAFLD tissue. Analysis of SREBP1 mRNA expression by quantitative PCR in (A) Primary human hepatocytes (PHH) incubated with 0.2 mM or 0.4 mM palmitate (Palm.) for 24 h, (B) PHH stimulated with TNF (10 ng/ml) for 24 h, (C) murine liver tissues from control mice (ctr.), mice fed a high fat diet leading to hepatic steatosis and mice fed a NASH inducing diet, and (D) liver tissue from patients with healthy livers (ctr.), steatosis without inflammation or NASH. (*p<0.05 compared to control (ctr.)).
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