Depletion of Liver Kupffer Cells Prevents the Development of Diet-Induced Hepatic Steatosis and Insulin Resistance

Abstract

OBJECTIVEIncreased activity of the innate immune system has been implicated in the pathogenesis of the dyslipidemia and insulin resistance associated with obesity and type 2 diabetes. In this study, we addressed the potential role of Kupffer cells (liver-specific macrophages, KCs) in these metabolic abnormalities.RESEARCH DESIGN AND METHODSRats were depleted of KCs by administration of gadolinium chloride, after which all animals were exposed to a 2-week high-fat or high-sucrose diet. Subsequently, the effects of these interventions on the development of hepatic insulin resistance and steatosis were assessed. In further studies, the effects of M1-polarized KCs on hepatocyte lipid metabolism and insulin sensitivity were addressed.RESULTSAs expected, a high-fat or high-sucrose diet induced steatosis and hepatic insulin resistance. However, these metabolic abnormalities were prevented when liver was depleted of KCs. In vitro, KCs recapitulated the in vivo effects of diet by increasing hepatocyte triglyceride accumulation and fatty acid esterification, and decreasing fatty acid oxidation and insulin responsiveness. To address the mechanisms(s) of KC action, we inhibited a panel of cytokines using neutralizing antibodies. Only neutralizing antibodies against tumor necrosis factor-α (TNFα) attenuated KC-induced alterations in hepatocyte fatty acid oxidation, triglyceride accumulation, and insulin responsiveness. Importantly, KC TNFα levels were increased by diet in vivo and in isolated M1-polarized KCs in vitro.CONCLUSIONSThese data demonstrate a role for liver macrophages in diet-induced alterations in hepatic lipid metabolism and insulin sensitivity, and suggest a role for these cells in the etiology of the metabolic abnormalities of obesity/type 2 diabetes.

Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes

“…Interestingly, as earlier described for adipose tissue macrophages, alternative M2 activation phenotype of Kupffer cells appears to ameliorate insulin resistance and to delay the progression to NASH in mice [46]. These data suggest that steatosis might induce a sub-acute inflammatory response in liver, similar to that observed in the adipose tissue inflammation following adipocyte lipid accumulation.…”

“…A c c e p t e d M a n u s c r i p t 8 production of inflammatory mediators that promote insulin resistance in liver [46]. Interestingly, as earlier described for adipose tissue macrophages, alternative M2 activation phenotype of Kupffer cells appears to ameliorate insulin resistance and to delay the progression to NASH in mice [46].…”

“…Unlike adipose tissue, the liver is densely populated with resident macrophages, the Kupffer cells, which account for over 10% of total liver cells. The number of Kupffer cells does not increase with obesity, but their activation state changes [45,46]. Although Kupffer cells have been less studied than adipose tissue macrophages in the context of insulin resistance, they clearly contribute to the…”

A novel murine model for non-alcoholic steatohepatitis developed by combination of a high-fat diet and oxidized low-density lipoprotein

“…We further observed that HFD exposure resulted in upregulated expression levels of TGF-b1 and collagen-a1 genes, as well as collagen synthesis, leading to slight hepatic fibrosis in the mice (Figures 2b and 5a-c, and Table 4). Other studies have showed that Kupffer cells (hepatic resident macrophages) are activated in diet-induced hepatic steatosis 42,43 and Kupffer cell-derived TGF-b1 initiates collagen production in hepatic stellate cells (HSCs). 44 It was also reported that lipid peroxidation in hepatocytes mediates the activation of HSCs in a rat model for hepatic fibrosis.…”

Antidiabetic effect of combined spices ofAllium sativum,Zingiber officinaleandCapsicum frutescensin alloxan-induced diabetic rats

“…In contrast, in diabetic control animals the lobular architecture was maintained, but there was also vacuolation of the hepatocytes, fatty deposits, sinusoidal dilation and congestion, mild portal inflammation, severe degeneration and necrosis. The observed degeneration of the hepatocytes in untreated diabetic rats could be attributed to insulin deficiency and suppression of mitochondrial β-oxidation of fatty acids, leading to deposition of triglycerides in the hepatocytes (Huang et al 2010). However, diabetic rats treated with combined spice extract or glibenclamide showed hepatocytes with nearly normal appearance and minimal necrosis.…”