TNF-Receptor-1 inhibition reduces liver steatosis, hepatocellular injury and fibrosis in NAFLD mice

Abstract

Non-alcoholic fatty liver disease (NAFLD) shows an increasing prevalence and is associated with the development of liver fibrosis and cirrhosis as the major risk factors of liver-related mortality in this disease. The therapeutic possibilities are limited and restricted to life style intervention, since specific drugs for NAFLD are unavailable so far. TNFα has been implicated as a major pathogenic driver of NAFLD. TNFα-mediated liver injury occurs mainly via TNF-receptor-1 (TNFR1) signaling, whereas TNFR2 mediates protective pathways. In this study, we analyzed the therapeutic effects of a novel antibody, which selectively inhibits TNFR1 while retaining protective TNFR2 signaling in a high-fat diet (HFD) mouse model of NAFLD. Mice were fed with HFD for 32 weeks and treated with anti-TNFR1-antibody or controlantibody for the last 8 weeks. We then investigated the mechanisms of TNFR1 inhibition on liver steatosis, inflammatory liver injury, insulin resistance and fibrosis. Compared to control-antibody treatment, TNFR1 inhibition significantly reduced liver steatosis and triglyceride content, which was accompanied by reduced expression and activation of the transcription factor SREBP1 and downstream target genes of lipogenesis. Furthermore, inhibition of TNFR1 resulted in reduced activation of the MAP kinase MKK7 and its downstream target JNK, which was associated with significant improvement of insulin resistance. Apoptotic liver injury, NAFLD activity and alanine aminotransferase (ALT) levels, as well as liver fibrosis significantly decreased by anti-TNFR1 compared to control-antibody treatment. Thus, our results suggest selective TNFR1 inhibition as a promising approach for NAFLD treatment.

Tumor necrosis factor alpha receptor 1 deficiency in hepatocytes does not protect from non-alcoholic steatohepatitis, but attenuates insulin resistance in mice

“…However, compared to lean controls, only Tnfr1 fl/fl mice had high blood glucose level after glucose and insulin challenge. Our observation that mice with a deficiency of Tnfr1 in hepatocytes are protected from insulin resistance, strengthens previous findings of Tnfr1 deficiency and improved insulin resistance[ 38 , 49 ]. TNF-mediated insulin resistance occurs via phosphorylation of the insulin receptor substrate IRS-1, which inhibits insulin-action in hepatocytes, and therefore promotes insulin resistance[ 39 , 40 ].…”

“…Higher serum level of soluble TNFR2 were detected in patients with HCC and hepatitis C[ 48 ]. The role of TNFR2 for NASH development is not conclusive, but it is thought to be protective[ 49 ].…”

Selective Targeting of TNF Receptors as a Novel Therapeutic Approach

“…Vice versa, in various diet-induced or genetic NAFLD models, TNF-or TNFR-deficient mice showed improved insulin sensitivity and less pronounced liver steatosis and fibrosis (Uysal et al, 1997(Uysal et al, , 1998Tomita et al, 2006). Our data show that blocking of TNFR1 by Atrosab results in alleviation of liver steatosis and insulin resistance as well as liver injury and fibrosis (Wandrer et al, 2020). Selective TNFR1 inhibition might therefore represent a promising treatment strategy in NAFLD.…”

Liver inflammation before spinal cord injury worsens neuropathology, hepatic injury, metabolic syndrome and locomotor deficits

“…Within the liver, TNFα can promote lipid accumulation by increasing expression of lipid uptake transporters such as CD36 and lipogenic molecules like serine palmitoyltransferase (SPT) and sterol regulatory response element bind protein-1c (SREBP-1c) (Endo et al ., 2007; Pagadala et al ., 2012; Martius et al ., 2015). Accordingly, a recent study using high fat diet-induced NAFLD showed inhibiting TNF receptor-1 reduced steatosis, SREBP-1c expression, overall indices of liver pathology (Wandrer et al ., 2020). Therefore, after SCI, SNS-induced TNFα expression may be a culprit in the elevated liver pathology.…”