Kupffer cell depletion protects against the steatosis, but not the liver damage, induced by marginal-copper, high-fructose diet in male rats

Abstract

High-fructose feeding impairs copper status and leads to low copper availability, which is a novel mechanism in obesity-related fatty liver. Copper deficiency-associated hepatic iron overload likely plays an important role in fructose-induced liver injury. Excess iron in the liver is distributed throughout hepatocytes and Kupffer cells (KCs). The aim of this study was to examine the role of KCs in the pathogenesis of nonalcoholic fatty liver disease induced by a marginal-copper high-fructose diet (CuMF). Male weanling Sprague-Dawley rats were fed either a copper-adequate or a marginally copper-deficient diet for 4 wk. Deionized water or deionized water containing 30% fructose (wt/vol) was also given ad libitum. KCs were depleted by intravenous administration of gadolinium chloride (GdCl3) before and/or in the middle of the experimental period. Hepatic triglyceride accumulation was completely eliminated with KC depletion in CuMF consumption rats, which was associated with the normalization of elevated plasma monocyte chemoattractant protein-1 (MCP-1) and increased hepatic sterol regulatory element binding protein-1 expression. However, hepatic copper and iron content were not significantly affected by KC depletion. In addition, KC depletion reduced body weight and epididymal fat weight as well as adipocyte size. Plasma endotoxin and gut permeability were markedly increased in CuMF rats. Moreover, MCP-1 was robustly increased in the culture medium when isolated KCs from CuMF rats were treated with LPS. Our data suggest that KCs play a critical role in the development of hepatic steatosis induced by marginal-copper high-fructose diet.

Regulation of tissue iron homeostasis: the macrophage “ferrostat”

“…Importantly, KCs highly express iron metabolism-associated genes and are transcriptionally regulated by SpiC and NRF2 (73). The location within sinusoids positions KCs as the primary cells that recycle iron released from nearby senescent erythrocytes, which may assist in dampening hepatocyte iron overload (74). Aberrant KC activation leads to increased proinflammatory cytokine release and subsequent hepatocyte hepcidin production, resulting in an overall decrease in iron export from the liver.…”

Depletion of myeloid cells exacerbates hepatitis and induces an aberrant increase in histone H3 in mouse serum

“…Impairment of the infiltration of CD11b‐positive monocytes delays the resolution of hepatic damage following acetaminophen‐induced liver injury in Ccr2 −/− mice compared with WT mice . Moreover, depletion of KCs by clodronate liposomes attenuates liver injuries triggered by lipopolysaccharide plus d ‐galactosamine, bile duct ligation, and diet‐induced hepatic steatosis . Notably, combined depletion of KCs and CD11b‐positive cells did not attenuate and instead exacerbated the phenotype of LysM‐DTR BM‐reconstituted Cflar Hep‐low mice compared with that of mice treated with DT alone (http://onlinelibrary.wiley.com/doi/10.1002/hep.28878/suppinfo and http://onlinelibrary.wiley.com/doi/10.1002/hep.28878/suppinfo).…”

Deficiency of myeloid-related proteins 8 and 14 (Mrp8/Mrp14) does not block inflammaging but prevents steatosis

“…This may be related to the intrinsic capacity of calprotectin to bind and transport fatty acids within hepatocytes or associated immune cell populations [52]. Any anergic effect of Mrp14-KO on Kupffer cells, in particular, may influence steatosis, since Kupffer cell depletion was previously shown to attenuate steatosis in rodents [53]. Within aging liver, Kupffer cells or other immune populations may also release pro-steatosis cytokines, such as IL-1β, TNF-α and IL-22 [54, 55], which disrupt bile acid synthesis and cholesterol efflux to promote cholesterol accumulation [55, 56].…”