Enhanced expression of pro-inflammatory mediators and liver X-receptor-regulated lipogenic genes in non-alcoholic fatty liver disease and hepatitis C

Abstract

NAFLD (non-alcoholic fatty liver disease) is one of the most frequent chronic liver diseases worldwide. The metabolic factors associated with NAFLD are also determinants of liver disease progression in chronic HCV (hepatitis C virus) infection. It has been reported that, besides inducing hepatic fatty acid biosynthesis, LXR (liver X receptor) regulates a set of inflammatory genes. We aimed to evaluate the hepatic expression of LXRα and its lipogenic and inflammatory targets in 43 patients with NAFLD, 44 with chronic HCV infection and in 22 with histologically normal liver. Real-time PCR and Western blot analysis were used to determine hepatic expression levels of LXRα and related lipogenic and inflammatory mediators in the study population. We found that the LXRα gene and its lipogenic targets PPAR-γ (peroxisome-proliferator-activated receptor-γ), SREBP (sterol-regulatory-element-binding protein)-1c, SREBP-2 and FAS (fatty acid synthase) were overexpressed in the liver of NAFLD and HCV patients who had steatosis. Moreover, up-regulation of inflammatory genes, such as TNF (tumour necrosis factor)-α, IL (interleukin)-6, OPN (osteopontin), iNOS (inducible NO synthase), COX (cyclo-oxygenase)-2 and SOCS (suppressors of cytokine signalling)-3, was observed in NAFLD and HCV patients. Interestingly, TNF-α, IL-6 and osteopontin gene expression was lower in patients with steatohepatitis than in those with steatosis. In conclusion, hepatic expression of LXRα and its related lipogenic and inflammatory genes is abnormally increased in NAFLD and HCV patients with steatosis, suggesting a potential role of LXRα in the pathogenesis of hepatic steatosis in these chronic liver diseases.

Liver X receptor α-mediated regulation of lipogenesis by core and NS5A proteins contributes to HCV-induced liver steatosis and HCV replication

“…The most interesting finding of this study is that HCV replication (genotype 1b) induced a LXRa-mediated intracellular lipid accumulation and lipogenic gene upregulation, supporting the results previously obtained in HCV patients. 21 In turn, we demonstrate that both HCV core and NS5A proteins contribute to the LXRamediated lipogenesis associated to HCV expression by indirect upregulation of LXRa through the PI3K pathway. Finally, we show that LXRa expression blockade or agonistmediated LXRa induction directly regulate HCV-induced lipogenesis and viral replication capacity.…”

“…For gene expression assays, cDNA was amplified using multiplex real-time PCR reactions on a StepOne Plus (Applied Biosystems). 21 TaqMan primers and probes were derived from the commercially available TaqMans Gene Expression Assays (Applied Biosystems) (Table 1). Relative changes in gene expression levels were determined using the 2 ÀDDCt method.…”

“…We have recently shown that the LXRa gene and its lipogenic targets PPAR-g, SREBP-1c, SREBP-2, fatty acid synthase (FAS), and fatty acid translocase CD36 are overexpressed in the liver of HCV genotype 1 patients. 21,22 Moreover, it has been described that HCV gene expression may activate the LXRa signaling pathway in in vivo and in vitro models. 15,23 Based on these data, it is conceivable that LXRa may be a key regulator of hepatic lipogenesis in HCV infection.…”

Protective effect of quercetin on high-fat diet-induced non-alcoholic fatty liver disease in mice is mediated by modulating intestinal microbiota imbalance and related gut-liver axis activation

“…Thus, in the current study LXR and its downstream lipogenic genes were overexpressed in HFD-fed mice. LXR plays a role as a contributing factor for NAFLD-related steatosis development by enhancing lipogenesis in in vivo and in vitro models and in the liver of patients [5,34]. This transcription factor increases fatty acid synthesis by either upregulating SREBP-1c or directly binding to the promoters of lipogenic genes, including fatty acid synthase [34].…”

Melatonin limits the expression of profibrogenic genes and ameliorates the progression of hepatic fibrosis in mice

“…Relative changes in gene expression levels were determined using the 2 2DDCt method. 25,26 The cycle number at which the transcripts were detec-table (Ct) was normalized to the cycle number of glyceraldehide-3-phosphate dehydrogenase gene detection, referred to as DCt.…”