Il-Whan Choi

Many studies have shown that TLR4- and TLR2-deficient mice are protected from high-fat diet-induced inflammation and insulin resistance, suggesting that saturated fatty acids derived from the high-fat diet activate TLR-mediated proinflammatory signaling pathways and induce insulin resistance. However, evidence that palmitic acid, the major dietary saturated fatty acid, can directly activate TLR has not been demonstrated. In this article, we present multiple lines of evidence showing that palmitic acid directly activates TLR2, a major TLR expressed on human monocytes, by inducing heterodimerization with TLR1 in an NADPH oxidase-dependent manner. Dimerization of TLR2 with TLR1 was inhibited by the n-3 fatty acid docosahexaenoic acid. Activation of TLR2 by palmitic acid leads to expression of pro-IL-1β that is cleaved by caspase-1, which is constitutively present in monocytes, to release mature IL-1β. Our results reveal mechanistic insight about how palmitic acid activates TLR2, upregulates NALP3 expression, and induces inflammasome-mediated IL-1β production in human monocytes, which can trigger enhanced inflammation in peripheral tissues, and suggest that these processes are dynamically modulated by the types of dietary fat we consume.

The potential anti-metastasis and anti-invasion activities of early growth response gene-1 (Egr-1) and claudin-3, a tight junction (TJ)-related protein, were evaluated using histone deacetylase (HDAC) inhibitors in human hepatocarcinoma cells. The results of wound healing and Transwell assays showed that HDAC inhibitors such as trichostatin A and sodium butyrate inhibited cell migration and invasion. HDAC inhibitors markedly induced Egr-1 expression during the early period, after which expression levels decreased. In addition, the down-regulation of snail and type 1 insulin-like growth factor receptor (IGF-1R) in HDAC inhibitor-treated cells induced the upregulation of thrombospondin-1 (TSP-1), E-cadherin and claudin-3. Cells transfected with Egr-1 and claudin-3 siRNA displayed significant blockage of HDAC inhibitor-induced anti-invasive activity. Collectively, these findings indicate that the up-regulation of Egr-1 and claudin-3 are crucial steps in HDAC inhibitor-induced anti-metastasis and anti-invasion.

Patterns of fatly acids released from milk fat and types of residual lipase activity in UHT milk were investigated. Commercial UHT milk samples obtained immediately after processing were stored at 23 and 35C and analyzed for both FFA and lipase activities. Results showed that concentrations of shortchain FFA, except lauric acid, changed little at 23C during 12 wk of storage. At 35C, however, concentrations of all short-chain FFA showed steady increases, ranging from 9% for caprylic to 45% for lauric acids. Concentrations of long-chain FFA increased moderately (7 to 20%) at 23C, but their increases were much higher (26 to 63%) at 35C. Patterns of release of FA were similar at both temperatures. However, the ratios of the long-chain FA released in UHT milk were different from those of FA of milk fat. Residual lipase activities were detected in UHT milks as well as in their centrifugal fractions. Cream fractions showed the highest lipase activities, followed by aqueous supernatant and casein precipitates. Cream fractions preferentially hydrolyzed long-chain FA from milk fat, whereas aqueous supernatant fractions hydrolyzed both short-chain and long-chain FA.