Adoptive transfer of Pfkfb3-disrupted hematopoietic cells to wild-type mice exacerbates diet-induced hepatic steatosis and inflammation

Abstract

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 ( Pfkfb3/ iPfk2) dissociates fat deposition and inflammation, the present study examined a role for Pfkfb3/ iPfk2 in hematopoietic cells in regulating hepatic steatosis and inflammation in mice. Methods: Pfkfb3 -disrupted ( Pfkfb3 +/−) mice and wild-type (WT) littermates were fed a high-fat diet (HFD) and examined for NAFLD phenotype. Also, bone marrow cells isolated from Pfkfb3 +/− 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- Pfkfb3 +/−) mice in which Pfkfb3 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. In vitro , 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 Pfkfb3 +/− mice displayed increased severity of liver inflammation in the absence of hepatic steatosis compared with HFD-fed WT mice. When inflammatory activation was analyzed, Pfkfb3 +/− macrophages revealed increased proinflammatory activation and decreased anti-proinflammatory activation. When NAFLD phenotype was analyzed in the chimeric mice, WT/BMT- Pfkfb3 +/− 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 Pfkfb3 +/− macrophages revealed increased fat deposition and proinflammatory responses compared with hepatocytes co-cultured with WT macrophages. Conclusions: Pfkfb3 disruption only in hematopoietic cells exacerbates HFD-induced hepatic steatosis and inflammation whereas the Pfkfb3/ iPfk2 in nonhematopoietic cells appeared to be needed for HFD feeding to induce hepatic steatosis. As such, the Pfkfb3/ iPfk2 plays a unique role in regulating NAFLD pathophysiology.

Palmitoleic acid on top of HFD ameliorates insulin resistance independent of diacylglycerols and alters gut microbiota in C57BL/6J mice

“…The liver is an important organ in glucose metabolism, which influences systemic glucose metabolism [52]. In HFD-fed mice, palmitoleic acid significantly decreased macrophage infiltration compared to BSA control and oleic acid treatment (Fig.…”

The Role of Palmitoleic Acid in Regulating Hepatic Gluconeogenesis through SIRT3 in Obese Mice

“…GTT, ITT, and PTT were performed as previously described [ 24 , 25 ]. Before the experiment, mice were fasted overnight (for GTT and PTT) or for 4 h (for ITT).…”

Recent Advances in Adipose Tissue Dysfunction and Its Role in the Pathogenesis of Non-Alcoholic Fatty Liver Disease

“…In addition, in an HFD-mouse model, liver steatosis, inflammation and IR can be dissociated in response to supplementation of palmitoleate (a monounsaturated fatty acid), which increases fat deposition in hepatocytes, but protects against the inflammatory response in both hepatocytes and macrophages [ 98 , 99 ]. In a recent study by Guo et al, it has been further validated that the PFKFB3 in adipocytes is needed, on the one side, for HFD feeding to induce hepatic steatosis, and, on the other side, for PFKFB3-driven adipocyte factors to suppress distal inflammation in the liver [ 100 ]. Clearly, PFKFB3 signifies how adipose tissue plays an essential role in regulating hepatic steatosis and liver inflammation, two key aspects of NAFLD/NASH.…”