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TMBIM1-dependent TLR4 degradation is a key regulator of NAFLD
Zhao GN, Zhang P, Gong J, et al. TMBIM1 is a multivesicular body regulator that protects against non-alcoholic fatty liver disease in mice and monkeys by targeting the lysosomal degradation of Tlr4. Nat Med 2017;23:742–52.
Toll-like receptor 4 (TLR4) signalling in non-alcoholic fatty liver disease (NAFLD) is associated with liver inflammation, insulin resistance and the metabolic syndrome. However, TLR4 also underpins important immunoregulatory and antimicrobial functions, making global TLR4 inhibition an unappealing long-term therapeutic strategy for patients. In this study, the authors have identified a role for transmembrane BAX inhibitor motif-containing 1 (TMBIM1) in regulating TLR4 degradation in hepatocytes, with resultant effects on NAFLD. TMBIM1 is a membrane protein, which is expressed in late endosomes and lysosomes. Hepatic TMBIM1 expression was reduced in both human and murine models of NAFLD, while knockout of TMBIM1 in hepatocytes exacerbated murine insulin resistance, hepatic steatosis and liver inflammation in response to a high-fat diet. Furthermore, hepatic overexpression of TMBIM1 protected mice against steatosis and liver inflammation. These beneficial effects of TMBIM1 were antagonised by TLR4, and the authors proceeded to demonstrate that TMBIM1 promotes TLR4 degradation via a multivesicular body endosomal-lysosomal pathway. Finally, in a monkey model of non-alcoholic steatohepatitis (NASH), viral overexpression of TMBIM1 in the liver resulted in reduced lipid accumulation, inflammation and fibrosis. Hence, TMBIM1 represents a potential therapeutic target for patients with NAFLD. Importantly, TMBIM1-dependent TLR4 degradation was only active in steatotic livers and not under basal conditions, potentially enabling the targeting of pathogenic TLR4 activity without the adverse effects of global TLR4 blockade.
Cancer stem cells: tracing the evidence
Shimokawa M, Ohta Y, Nishikori S, et al. Visualization and targeting of LGR5+ human colon cancer stem cells. Nature 2017;545:187–92.
The cancer stem cell (CSC) theory is based on a hierarchy of cell types within cancer, with only CSCs being able to self-renew and sustain cancer …
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