Docosahexaenoic acid ameliorates palmitate-induced lipid accumulation and inflammation through repressing NLRC4 inflammasome activation in HepG2 cells

Abstract

BackgroundN-3 polyunsaturated fatty acids, such as docosahexaenoic acid (DHA; 22:6n-3), has clinical significance in the prevention and reversal of nonalcoholic steatohepatitis (NASH). However, the precious mechanism underlying remains unclear. The inflammasome, a multiprotein complex formed by NOD-like receptor (NLR) family members, has been recently shown to be activated in NASH and promote the cleavage of the pro-inflammatory cytokines to their maturation forms.MethodsHepG2 cells were exposed to different dose of PA for 24 h with or without the preincubation of 50 μM DHA for another 24 h and then lipid deposition was assessed with Oil red O staining and intracellular triglyceride (TG) determination. Secretory levels of inflammatory cytokines and Caspase-1 activity were determined by ELISA assays. Gene expression and protein levels were determined by quantitative RCR and western blotting, respectively.ResultsPalmitate (PA) dose-dependently increased lipid accumulation, TG content and induced the secretion of interleukin-1β (IL-1β), IL-18, TNF-α and MCP-1 from HepG2 cells. Preincubation with DHA significantly alleviated PA-induced lipid accumulation and inflammatory agents. DHA was also found to attenuate PA-induced NOD-like receptor protein 4 (NLRC4) mRNA expression. Furthermore, PA induced caspase-1 activation in a dose-dependent manner, resulting in exacerbating of procaspase-1 and pro-IL-1β processing. Knockdown of NLRC4 partially abrogated PA-induced caspase-1 activation and IL-1β maturation and completely abolished these events in the presence of DHA.ConclusionsOur findings indicate DHA attenuates PA-induced lipid accumulation and inflammation through suppressing NLRC4 inflammasome activation, caspase-1 activation and IL-1β cleavage.

The role of inflammasome in Alzheimer's disease

“…In addition, NLRC4 and ASC levels are upregulated in the brains of AD patients (Liu and Chan, 2014), suggesting a possible role of the NLRC4 inflammasome in AD pathogenesis. In support, palmitate induces IL-1β release from HepG2 (hepatocellular carcinoma cells), and knockdown of NLRC4 inhibits the palmitate induced inflammation and cytokine release (Cho et al, 2013; Luo et al, 2012). Fatty acids can also cause the release of IL-1β from microglia, but the specific inflammasome that regulates this process has not been identified (Wang et al, 2012).…”

“…Palmitate, the most common saturated fatty acid in the diet (Guo et al, 2007), triggers the production of cytokines, in particular IL-1β, from many cell types, including astrocytes (Liu et al, 2013a; Luo et al, 2012). Recently we identify that palmitate activates the NLRC4 inflammasomein primary astrocytes to release IL-1β, and ASC participates in the activation of the NLRC4 inflammasome (Liu and Chan, 2014).…”

Efeitos do ácido docosahexaenoico (DHA) e do ácido araquidônico (AA) sobre a morte celular da linhagem celular de câncer de mama MDA-MB-231

“…No câncer, um único estudo mostrou que o DHA inibiu a ativação do inflamassoma induzida por palmitato em células de carcinoma hepatocelular (53). A ativação do inflamassoma NLRP3 se dá por diversas moléculas derivadas de patógenos ou do próprio hospedeiro, enquanto que o NLRP1b, o NLRC4 e o AIM2 são ativados por componentes bacterianos ou virais.…”

“…Os monócitos possuem caspase 1 ativa constitutivamente e o primeiro sinal é suficiente para a ativação das citocinas pró-inflamatórias, já os macrófagos necessitam de dois sinais para a ativação do inflamassoma (55) O palmitato é capaz de ativar o inflamassoma NLRC4 em células de carcinoma hepatocelular e a diminuição da expressão dessa proteína não anula a secreção de IL-1β induzida pelo ácido graxo. Isso mostra que outros inflamassomas também são ativados pelo palmitato na célula tumoral (53).…”

A randomized controlled trial investigating the neurocognitive effects of Lacprodan® PL-20, a phospholipid-rich milk protein concentrate, in elderly participants with age-associated memory impairment: the Phospholipid Intervention for Cognitive Ageing Reversal (PLICAR): study protocol for a randomized controlled trial

“…Previous research suggests that milk proteins may increase insulin secretion, as well as help to reduce blood pressure and plasma cholesterol levels [3,97]. Further, high levels of B12 present in milk may also help to lower HCy levels, which are a contributing factor to CV disease [98].…”