Intracellular lipid content is a key intrinsic determinant for hepatocyte viability and metabolic and inflammatory states in mice

Abstract

Sheng L, Jiang B, Rui L. Intracellular lipid content is a key intrinsic determinant for hepatocyte viability and metabolic and inflammatory states in mice. Am J Physiol Endocrinol Metab 305: E1115-E1123, 2013. First published August 27, 2013 doi:10.1152/ajpendo.00401.2013The liver is an essential metabolic organ. In addition to metabolizing glucose and lipids, hepatocytes also secrete various cytokines that modulate both hepatocyte metabolism and liver inflammation. Hepatocyte injury and death and liver inflammation are the major contributors to liver diseases, including nonalcoholic steatohepatitis (NASH). Anatomic locations have a profound effect on hepatocyte metabolism, and liver zonation describes the metabolic heterogeneity of hepatocytes along the portovenous axis. However, it is unclear whether hepatocyte heterogeneity is affected by intrinsic factors and whether dietary fat, a risk factor for NASH, has distinct detrimental effects on different hepatocyte subpopulations. Here, we showed that mouse livers contained both high-lipid and low-lipid subpopulations of hepatocytes. The high-lipid subpopulation was more susceptible to injury and apoptosis and produced more proinflamatrory cytokines after treatment with endotoxin and saturated fatty acids. Dietary fat consumption further increased fatty acid uptake, intracellular lipid levels, hepatocyte injury and death, and the expression of proinflammatory cytokines in the high-lipid subpopulation. In contrast, dietary fat slightly increased lipid levels, cell death, and expression of proinflammatory cytokines in the low-lipid subpopulation. The lowlipid subpopulation produced more glucose. Fat consumption further activated the gluconeogenic program in the low-lipid, but not the high-lipid, subpopulations. These data suggest that intracellular lipid content is a key intrinsic determinant for hepatocyte heterogeneity of metabolic, inflammatory, and survival states.

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“…Substantive organ inflammatory disease generally involves extensive parenchymal cell injury, which is considered to be involved in regulation of inflammation 6 31 32 33 34 . It has been described that hepatocytes are involved in ethanol-induced liver injury by releasing the endogenous danger molecules, uric acid and ATP, which are recognized by liver immune cells 33 .…”

“…Liver injury, usually induced by heavy alcohol consumption, drug abuse, and virus infection, is a common clinical disease characterized by hepatocyte injury 3 4 5 . Recently, many studies have shown that injured hepatocytes can secrete important cytokines and chemokines that are involved in the immune response, by activating and recruiting immunocytes 2 6 7 . Although the cytokines and chemokines secreted by injured hepatocytes have been considered to participate in liver injury 6 , the molecular mechanism of how these cytokines and chemokines are produced from injured hepatocytes is still indistinct.…”

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“…Values are presented as means Ϯ SE. *P Ͻ 0.05. bone marrow-derived macrophages (BMDMs) as described previously (22). BMDMs were treated without or with LPS (20 ng/ml) for 4 h and washed extensively with PBS and cultured in fresh growth medium.…”

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“…Hepatocytes, which are major parenchymal cells in the liver, play pivotal roles in metabolism, detoxification, and protein synthesis. Hepatocytes can accumulate triglyceride by increasing fatty acid uptake and de novo lipogenesis, and metabolize fatty acids through lipolysis [13]. Kupffer cells, the resident macrophage in the liver, play an integral role in the hepatic immune response [14].…”