Adoptive transfer of -disrupted hematopoietic cells to wild-type mice exacerbates diet-induced hepatic steatosis and inflammation.

BACKGROUND AND OBJECTIVES

Hepatic steatosis and inflammation are key characteristics of non-alcoholic fatty liver disease (NAFLD). However, whether and how hepatic steatosis and liver inflammation are differentially regulated remains to be elucidated. Considering that disruption of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (iPfk2) dissociates fat deposition and inflammation, the present study examined a role for iPfk2 in hematopoietic cells in regulating hepatic steatosis and inflammation in mice.

METHODS

-disrupted ( mice and wild-type (WT) littermates were fed a high-fat diet (HFD) and examined for NAFLD phenotype. Also, bone marrow cells isolated from mice and WT mice were differentiated into macrophages for analysis of macrophage activation status and for bone marrow transplantation (BMT) to generate chimeric (WT/BMT- mice in which was disrupted only in hematopoietic cells and control chimeric (WT/BMT-WT) mice. The latter were also fed an HFD and examined for NAFLD phenotype. , hepatocytes were co-cultured with bone marrow-derived macrophages and examined for hepatocyte fat deposition and proinflammatory responses.

RESULTS

After the feeding period, HFD-fed mice displayed increased severity of liver inflammation in the absence of hepatic steatosis compared with HFD-fed WT mice. When inflammatory activation was analyzed, macrophages revealed increased proinflammatory activation and decreased anti-proinflammatory activation. When NAFLD phenotype was analyzed in the chimeric mice, WT/BMT- mice displayed increases in the severity of HFD-induced hepatic steatosis and inflammation compared with WT/BMT-WT mice. At the cellular level, hepatocytes co-cultured with macrophages revealed increased fat deposition and proinflammatory responses compared with hepatocytes co-cultured with WT macrophages.

CONCLUSIONS

disruption only in hematopoietic cells exacerbates HFD-induced hepatic steatosis and inflammation whereas the iPfk2 in nonhematopoietic cells appeared to be needed for HFD feeding to induce hepatic steatosis. As such, the iPfk2 plays a unique role in regulating NAFLD pathophysiology.