Targeting arginase-II protects mice from high-fat-diet-induced hepatic steatosis through suppression of macrophage inflammation

Abstract

Nonalcoholic fatty liver disease (NAFLD) associates with obesity and type 2 diabetes. Hypoactive AMP-activated protein kinase (AMPK), hyperactive mammalian target of rapamycin (mTOR) signaling, and macrophage-mediated inflammation are mechanistically linked to NAFLD. Studies investigating roles of arginase particularly the extrahepatic isoform arginase-II (Arg-II) in obesity-associated NAFLD showed contradictory results. Here we demonstrate that Arg-II−/− mice reveal decreased hepatic steatosis, macrophage infiltration, TNF-α and IL-6 as compared to the wild type (WT) littermates fed high fat diet (HFD). A higher AMPK activation (no difference in mTOR signaling), lower levels of lipogenic transcription factor SREBP-1c and activity/expression of lipogenic enzymes were observed in the Arg-II−/− mice liver. Moreover, release of TNF-α and IL-6 from bone marrow-derived macrophages (BMM) of Arg-II−/− mice is decreased as compared to WT-BMM. Conditioned medium from Arg-II−/−-BMM exhibits weaker activity to facilitate triglyceride synthesis paralleled with lower expression of SREBP-1c and SCD-1 and higher AMPK activation in hepatocytes as compared to that from WT-BMM. These effects of BMM conditioned medium can be neutralized by neutralizing antibodies against TNF-α and IL-6. Thus, Arg-II-expressing macrophages facilitate diet-induced NAFLD through TNF-α and IL-6 in obesity.

Disruption of adenosine 2A receptor exacerbates NAFLD through increasing inflammatory responses and SREBP1c activity

“…Because the initial differences among cocultures existed solely in macrophages (e.g., the presence or absence of A 2A R), the outcomes of hepatocyte lipogenic events were attributable to the effects secondary to A 2A R disruptionassociated increase in macrophage proinflammatory activation. The latter has been shown to generate macrophage-derived factors (i.e., proinflammatory cytokines) to promote hepatocyte lipogenic events, (14) enhance hepatocyte proinflammatory responses, and decrease hepatocyte insulin signaling. (33) Therefore, the results from myeloid cell-specific A 2A R-deficient mice and macrophage-hepatocyte cocultures demonstrate that A 2A R has a role in coordinating macrophage actions on hepatocytes to protect against NAFLD aspects.…”

Genetic Targeting of Arginase-II in Mouse Prevents Renal Oxidative Stress and Inflammation in Diet-Induced Obesity

“…The increase in Arg-II in macrophages under HFD feeding promotes pro-inflammatory responses, contributing to obesity-associated glucose intolerance, insulin resistance, and nonalcoholic fatty liver diseases (NAFLD) as well as atherogenesis (Ming et al, 2012; Liu et al, 2016). In kidney, we demonstrate in this study that Arg-II is mainly expressed in the S3 straight segment of the proximal tubules as demonstrated by expression in the B0AT3 positive cells.…”

“…It is important to point out that the Arg-II −/− mice are protected from whole body glucose intolerance with improved insulin sensitivity and less NAFLD on HFD (Liu et al, 2016). Similar to the liver, we also found a decreased renal lipid accumulation in kidney as shown in our current study.…”

L-Norvaline, a New Therapeutic Agent against Alzheimer’s disease

“…Worth mentioning that ARG2 deficiency extends the lifespan of mice (Xiong et al, 2017). Moreover, targeting ARG2 protects mice from high-fat-diet-induced hepatic steatosis through suppression of macrophage inflammation (Liu et al, 2016). Interestingly enough, the release of TNFα from bone marrow-derived macrophages of Arg2 −/− mice is decreased as compared to the WT animals.…”