Dietary Saturated Fat Promotes Development of Hepatic Inflammation Through Toll‐Like Receptor 4 in Mice

Abstract

Nonalcoholic steatohepatitis (NASH) is currently the third most common cause of end stage liver disease necessitating transplantation. The question remains how inflammation and NASH develop in the setting of nonalcoholic fatty liver disease (NAFLD) and steatosis. Understand the roles of toll-like receptor 4 (TLR4) and dietary fats in the development of hepatic inflammation. Wild-type and TLR4 KO mice were fed a standard high fat diet (LD), a high saturated fat diet (MD), or an isocaloric control diet (CD). Sera and tissue were analyzed for development of hepatic steatosis, inflammation, and injury. MD induced features of hepatic steatosis and inflammation in wild-type, but not in TLR4 KO, mice. TLR4 KO prevented MD induced increases in NAFLD activity scores, serum alanine aminotransferase levels, and inflammatory cytokine expression. Inflammatory cell infiltration and cytokine expression were also lower in the TLR4 KO mice livers than wild-type mice fed MD. Hepatic expression of Collagen I transcripts and collagen deposition were also decreased in the TLR4 KO MD animals. Results show that TLR4 plays a critical role in the effects of dietary fat composition on the development of hepatic steatosis, inflammation, and injury consistent with nonalcoholic steatohepatitis.

Obese diet-induced mouse models of nonalcoholic steatohepatitis-tracking disease by liver biopsy

“…In line with previous findings in diet-induced NASH mouse models [26] , we observed increased expression of TLR4, a key receptor in fibrogenic development as demonstrated in high-fat diet-induced TLR4 knockout [22] , and bile duct ligation models [23] . In addition, TLR4 KO in ob/ob mice was protective against NASH development as evinced by reduced NAS compared to regular ob/ob mice [27] .…”

“…Similar analyses were conducted on a subset of samples from ob/ob-NASH animals which confirmed the exaggerated expression levels of collagen types ( Figure 2E). The pathway analysis also highlighted TLR signaling as one of the primary affected signaling processes, an observation supported by the increased expression of TLR4, which was recently demonstrated as an important pro-inflammatory mediator in the pathogenesis of NASH [22,23] . Notably, mRNA expression levels of a number of other TLR subtypes (TLR7, TLR8, TLR12 and TLR13) were upregulated to greater extent than TLR4 ( Figure 2F).…”

Efeito da ingestão das gorduras interesterificadas sobre vias inflamatórias e metabólicas no fígado e tecido adiposo de camundongos LDLr-KO

“…A última etapa deste trabalho foi identificar o impacto das gorduras interesterificadas sobre o metabolismo de lípides hepáticos, uma vez que dieta rica em gordura, principalmente em ácidos graxos saturados, desempenha importante papel na progressão da NAFLD (Westerbacka et al, 2005;Sutter et al, 2015), podendo progredir para inflamação e fibrose (Liu et al, 2016).…”

“…Os processos de fibrose e apoptose são eventos tardios durante a progressão da NAFLD (Sutter et al, 2015), que ocorrem geralmente após maior grau de inflamação (Kumar et al, 2010). Isso pode explicar a menor secreção de TNFα e IL-1β, em comparação a PALM.…”

“…Juntos, esses fatores contribuem para a progressão da NAFLD e incorrem em um quadro de NASH (Sutter et al, 2015), cujas características histopatológicas são esteatose com lesão hepatocelular, inflamação e vários graus de fibrose (Liu et al, 2016), além de corpos de Mallory, acúmulo de neutrófilos ao redor do hepatócito e de linfócitos e macrófagos no parênquima hepático (Kumar et al, 2010). Por esses motivos, a fisiopatologia de NASH está fortemente associada ao aumento de biomarcadores inflamatórios, lipotoxicidade e estresse oxidativo e do retículo endoplasmático (Cusi, 2009).…”