Dietary Factors Alter Hepatic Innate Immune System in Mice With Nonalcoholic Ratty Liver Disease * #

Abstract

Dietary factors promote obesity and obesity-related disorders, such as fatty liver disease. Natural killer T (NKT) cells are components of the innate immune system that regulate proinflammatory (Th-1) and anti-inflammatory (Th-2) immune responses. Previously, we noted that NKT cells are selectively reduced in the fatty livers of obese, leptin-deficient ob/ob mice and demonstrated that this promotes proinflammatory polarization of hepatic cytokine production, exacerbating lipopolysaccharide (LPS) liver injury in these animals. In the current study, we show that hepatic NKT cells are also depleted by diets that induce obesity and fatty livers in wild-type mice, promoting Th-1 polarization of hepatic cytokine production and sensitization to LPS liver injury despite persistent leptin. Adult male C57BL6 mice fed diets containing high amounts of either fat or sucrose, or combined high-fat, highsucrose, develop increased hepatic NKT cell apoptosis and reduced liver NKT cells. The hepatic lymphocytes are more Th-1 polarized with increased intracellular interferon gamma and tumor necrosis factor alpha. Mice fed high-fat diets also exhibit more liver injury, reflected by 2-fold greater serum alanine aminotransferase (ALT) than control animals after receiving LPS. In conclusion, when otherwise normal mice are fed with high-fat or sucrose diet, they become obese, develop fatty livers, and acquire hepatic innate immune system abnormalities, including increased NKT cell apoptosis. The latter reduces liver NKT cell populations and promotes excessive hepatic production of Th-1 cytokines that promote hepatic inflammation. These diet-induced alterations in the hepatic innate immune system may contribute to obesity-related liver disease. (HEPATOLOGY 2005;42:880-885.)

Natural killer T cells and non-alcoholic fatty liver disease: Fat chews on the immune system

“…A growing body of experimental data demonstrates a link between hepatosteatosis and defects in NKT numbers and/or function. Over the past years, reductions in NKT cell numbers was reported in the fatty liver by a number of groups including ours [2][3][4] . Observations by our group show an inverse correlation between hepatic NKT cell numbers with the accumulation of hepatic lipid using the choline-deficient diet model of hepatosteatosis [4] .…”

Hepatic stereology of schistosomiasis mansoni infected-mice fed a high-fat diet

“…Because parasite surface-bound host LDL, it may provides the schistosome with cholesterol and other lipids, as well as aid immune avoidance, understanding this process may provide fundamental insights into lipid metabolism and host defense in schistosomes (Furlong & Caulfield 1988, Tempone et al 1997, Bica et al 2000. More- disease or steatosis (Biddinger et al 2005, Li et al 2005), a histopathologic condition characterized by an excess accumulation of lipids, primarily triacylglycerol (TG), within hepatocytes (Burt et al 1998). In addition, mice fed highfat acquire hepatic innate immune system abnormalities (Li et al 2005).…”

“…More- disease or steatosis (Biddinger et al 2005, Li et al 2005), a histopathologic condition characterized by an excess accumulation of lipids, primarily triacylglycerol (TG), within hepatocytes (Burt et al 1998). In addition, mice fed highfat acquire hepatic innate immune system abnormalities (Li et al 2005). Hence, the progression of liver injury in mice fed HFD is of likely pathophysiological relevance.…”

“…Dietary factors promote obesity and obesity-related disorders, such as fatty liver disease (Li et al 2005). Obesity is also predictive of the presence of fibrosis, potentially progressing to advanced liver disease (Festi et al 2004).…”

C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet

“…Genetically obese rodents quickly develop steatohepatitis after exposure to low doses of LPS [12], while polymyxin B diminishes hepatic steatosis during total parenteral nutrition in the rat by reducing caecal flora [13]. Moreover, endotoxins exert a strong effect on liver of mice fed a high-fat diet [14].…”