Hepatic IL-1 signaling in NAFLD is a driver of whole-body insulin resistance and adipose tissue inflammation.

Question:

There is emerging evidence supporting the concept that low-grade, chronic metabolic inflammation – to a large degree emanating from the hepatic compartment of patients with non-alcoholic fatty liver disease (NAFLD) – is a driving force of extrahepatic comorbidities. This study examines the role of hepatic interleukin (IL)-1 signaling as a trigger of systemic insulin resistance and inflammation.

Methods:

8 – 10-week-old male hepatocyte-specific IL-1 receptor type 1 (IL-1R1) knockout mice (Il1r1 ^Hep-/-) and their wild-type (WT) littermates were fed a high-fat, high-carbohydrate diet (HFD) for 12 weeks to induce obesity-related NAFLD or a control diet.

Results:

All mice fed the HFD developed an obese phenotype – characterized by a significant weight gain and associated systemic metabolic alterations (hyperlipidemia, hyperglycemia and decreased adiponectin levels) – and an accompanying macrovesicular hepatic steatosis. Despite comparable metabolic stress induced by HFD, levels of serum transaminases, hepatic microvesicular steatosis and activation of c-Jun N-terminal kinases (JNK) and extracellular signal-regulated kinases (ERK) were significantly higher in the WT compared to Il1r1 ^Hep-/- mice, suggesting a different pattern of liver injury and mitochondrial function. Moreover, Il1r1 ^Hep-/- mice on HFD displayed an improvement of both hepatic and peripheral insulin sensitivity as evidenced by increases in hepatic insulin receptor expression and Akt (Ser473) phosphorylation, reduced fasting insulin and HOMA-IR levels and improved whole-body glucose tolerance following intraperitoneal glucose challenge. This was accompanied by reduced adipose tissue inflammation as reflected by decreased gene expression of F4/80, monocyte chemotactic protein (MCP)-1 and IL-1 receptor antagonist (IL-1RA) in Il1r1 ^Hep-/- mice compared to WT mice.

Conclusions:

This data suggests a pivotal role of the IL-1R1 signaling pathway in hepatocytes in controlling whole-body insulin sensitivity and adipose tissue inflammation in the context of increasing metabolic burden.