Enhanced Palmitate-Induced Interleukin-8 Formation in Human Macrophages by Insulin or Prostaglandin E2.

Macrophages in pathologically expanded dysfunctional white adipose tissue are exposed to a mix of potential modulators of inflammatory response, including fatty acids released from insulin-resistant adipocytes, increased levels of insulin produced to compensate insulin resistance, and prostaglandin E2 (PGE2) released from activated macrophages. The current study addressed the question of how palmitate might interact with insulin or PGE2 to induce the formation of the chemotactic pro-inflammatory cytokine interleukin-8 (IL-8). Human THP-1 cells were differentiated into macrophages. In these macrophages, palmitate induced IL-8 formation. Insulin enhanced the induction of IL-8 formation by palmitate as well as the palmitate-dependent stimulation of PGE2 synthesis. PGE2 in turn elicited IL-8 formation on its own and enhanced the induction of IL-8 release by palmitate, most likely by activating the EP4 receptor. Since IL-8 causes insulin resistance and fosters inflammation, the increase in palmitate-induced IL-8 formation that is caused by hyperinsulinemia and locally produced PGE2 in chronically inflamed adipose tissue might favor disease progression in a vicious feed-forward cycle.

Direct and indirect modulation of LPS-induced cytokine production by insulin in human macrophages.

Overweight and obesity are accompanied by insulin resistance, impaired intestinal barrier function resulting in increased lipopolysaccharide (LPS) levels, and a low-grade chronic inflammation that results in macrophage activation. Macrophages produce a range of interleukins as well as prostaglandin E2 (PGE2). To cope with insulin resistance, hyperinsulinemia develops. The purpose of the study was to elucidate how LPS, insulin and PGE2 might interact to modulate the inflammatory response in macrophages. Human macrophages were either derived by differentiation from U937 cells or isolated from blood mononuclear cells. The macrophages were stimulated with LPS, insulin and PGE2. Insulin significantly enhanced the LPS-dependent expression of interleukin-1ß and interleukin-8 on both the mRNA and protein levels. Additionally, insulin increased the LPS-dependent induction of enzymes involved in the PGE2-synthesis and the production of PGE2 by macrophages. PGE2 in turn further enhanced the LPS-dependent expression of cytokines via its Gs-coupled receptors EP2 and EP4, the latter of which appeared to be more relevant. The combination of all three stimuli resulted in an even higher induction than the combination of LPS plus insulin or LPS plus PGE2. Thus, the compensatory hyperinsulinemia might directly and indirectly enhance the LPS-dependent cytokine production in obese individuals.

Soybean Oil-Derived Poly-Unsaturated Fatty Acids Enhance Liver Damage in NAFLD Induced by Dietary Cholesterol.

While the impact of dietary cholesterol on the progression of atherosclerosis has probably been overestimated, increasing evidence suggests that dietary cholesterol might favor the transition from blunt steatosis to non-alcoholic steatohepatitis (NASH), especially in combination with high fat diets. It is poorly understood how cholesterol alone or in combination with other dietary lipid components contributes to the development of lipotoxicity. The current study demonstrated that liver damage caused by dietary cholesterol in mice was strongly enhanced by a high fat diet containing soybean oil-derived ω6-poly-unsaturated fatty acids (ω6-PUFA), but not by a lard-based high fat diet containing mainly saturated fatty acids. In contrast to the lard-based diet the soybean oil-based diet augmented cholesterol accumulation in hepatocytes, presumably by impairing cholesterol-eliminating pathways. The soybean oil-based diet enhanced cholesterol-induced mitochondrial damage and amplified the ensuing oxidative stress, probably by peroxidation of poly-unsaturated fatty acids. This resulted in hepatocyte death, recruitment of inflammatory cells, and fibrosis, and caused a transition from steatosis to NASH, doubling the NASH activity score. Thus, the recommendation to reduce cholesterol intake, in particular in diets rich in ω6-PUFA, although not necessary to reduce the risk of atherosclerosis, might be sensible for patients suffering from non-alcoholic fatty liver disease.