Toll-like receptor 7 affects the pathogenesis of non-alcoholic fatty liver disease

Kim, Sokho; Park, Surim; Kim, Bumseok; Kwon, Jungkee

doi:10.1038/srep27849

Cited by 35 publications

(26 citation statements)

References 50 publications

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“…However, the mechanisms that contribute to progression to acute AH remain unclear. In mouse hepatocytes, fat accumulation was associated with decreased TLR 7 expression (Kim et al., ); however, in our human liver biopsy studies, NASH did not show decreased TLR 7 mRNA expression. Our research indicates that both the TLR 7 receptor and let‐7 micro RNA s, endogenous ligands of TLR 7, are increased in patients with AH .…”

Section: Discussioncontrasting

confidence: 74%

“…Previous studies have reported altered hepatocyte TLR7 expression in patients with liver disease (Firdaus et al., ; Leake, ; Lee et al., ; Lin et al., ), including end‐stage alcoholic cirrhosis (Starkel et al., ), and have found TLR7 responses in hepatocyte cell lines (e.g., HepG2, Huh‐7) (Lee et al., ; Sarkar et al., ). Interestingly, unsaturated fatty acids reduce TLR7 expression, increase insulin‐like growth factor 1 (IGF1), and increase oxidative stress in mouse hepatocytes and genetic ablation of TLR7 led to fatty liver, reactive free radicals, and IGF1 up‐regulation in TLR7 knockout mice, consistent with the involvement of TLR7 in hepatic fat accumulation (Kim et al., ). TLR7 responds to ssRNA, including viral ssRNA such as hepatitis C virus (HCV) (Negash et al., ), linking TLR7 to chronic viral hepatitis‐associated cirrhosis HCC.…”

Section: Discussionmentioning

confidence: 78%

“…Indeed, hepatocytes may be uniquely involved in hepatic TLR7 signaling due to their susceptibility to HCV infection, a ssRNA virus that activates hepatocyte TLR7 and induces inflammatory responses (e.g., TNF α induction) in hepatocytes. In mouse hepatocytes, TLR7 can induce autophagy responses through IGF1 that are Myd88 dependent and reduced by fat accumulation (Kim et al., ). In this study, EtOH induced TLR7 mRNA expression in both mice and in cultured hepatocytes, whereas imiquimod, the TLR7 agonist, did not increase the receptor's mRNA expression at the time points studied.…”

Section: Discussionmentioning

confidence: 99%

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TLR7‐let‐7 Signaling Contributes to Ethanol‐Induced Hepatic Inflammatory Response in Mice and in Alcoholic Hepatitis

Massey

Qin

Cabezas

et al. 2018

Alcoholism Clin & Exp Res

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BackgroundToll‐like receptor 7 (TLR7) is an endosomal TLR that is activated by single‐stranded RNA, including endogenous microRNAs (e.g., let‐7b). Increased hepatic expression of TLRs, microRNAs, and inflammatory mediators is linked to ethanol (EtOH) exposure and to alcoholic liver disease (ALD). ALD invovles chronic hepatic inflammation that can progress to alcoholic hepatitis (AH), a particularly severe form of ALD. This study aimed to investigate TLR7 expression in patients with different liver disease phenotypes and in mouse liver following alcohol exposure.MethodsHepatic mRNA expression was determined by RNA sequencing of liver tissue from patients with liver disease or normal liver tissue. Mice were exposed to subchronic EtOH followed by administration of the TLR7 agonist imiquimod. Primary human hepatocytes were exposed to EtOH or imiquimod in vitro.Results RNAseq analysis revealed that hepatic expression of TLR7 and let‐7b microRNA, an endogenous TLR7 ligand, was significantly increased in AH patients. Hepatic expression of TLR7 and let‐7b positively correlated with hepatic IL‐8 mRNA expression. In mice, EtOH increased hepatic TLR7 mRNA expression and enhanced imiquimod‐induced expression of the pro‐inflammatory mediators TNF α, MCP‐1, and iNOS. In vitro, EtOH significantly increased hepatocyte TLR7 mRNA and the TLR7 agonist, imiquimod, induced hepatocyte expression of TNF α and IL‐8 mRNA. EtOH also increased the release of let‐7b in microvesicles from hepatocytes, suggesting that EtOH can increase the expression of both the receptor and its endogenous ligand.ConclusionsThese studies suggest that increased TLR7 signaling caused by increased expression of TLR7 and its endogenous ligand let‐7b may contribute to the enhanced inflammatory response associated with AH.

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Section: Discussioncontrasting

confidence: 74%

Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

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TLR7‐let‐7 Signaling Contributes to Ethanol‐Induced Hepatic Inflammatory Response in Mice and in Alcoholic Hepatitis

Massey

Qin

Cabezas

et al. 2018

Alcoholism Clin & Exp Res

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“…NAFLD patients are at increased risk of liver-related diseases and have an elevated risk of cardiovascular disease and mortality, and NAFLD is rapidly becoming the leading indication for liver transplantation [2]. The mechanism underlying NAFLD pathophysiology remains elusive; however, a "two-hit" hypothesis has been suggested as a possible mechanism of pathological change in chronic liver disease [3]. Simple hepatic steatosis caused by lipid accumulation represents the "first hit" in the pathological process [4].…”

Section: Introductionmentioning

confidence: 99%

Resveratrol Ameliorates Lipid Droplet Accumulation in Liver Through a SIRT1/ ATF6-Dependent Mechanism

Zhou

et al. 2018

Cell Physiol Biochem

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Background/Aims: Lipid droplets (LDs) are dynamic organelles that store neutral lipids during times of energy excess, and an increased accumulation of LDs in the liver is closely linked to hepatic steatosis. Our previous studies suggested that resveratrol (RSV) supplement could improve hepatic steatosis, but the underlying mechanism, particularly which related to LD accumulation, has not yet been elucidated. Methods: A high-fat diet (HFD) and palmitic acid were used to induce hepatic steatosis in mouse liver and hepatocytes, respectively. The effects of RSV on LD accumulation were analyzed in vivo and in vitro. The effects of RSV on the expression levels of LD-associated genes (ATF6, Fsp27β/CIDEC, CREBH, and PLIN1) were measured by qRT-PCR and western blot assays, followed by KD or overexpression of SIRT1 and ATF6 with small interfering RNAs or overexpressed plasmids, respectively. The dual luciferase reporter assay, chromatin immunoprecipitation assay, coimmunoprecipitation, and proximity ligation assay were utilized to clarify the mechanism of transcriptional regulation and possible interaction between SIRT1 and ATF6. Results: There was a significant increase in the accumulation of LDs in liver and hepatocytes during the process of HFD-induced steatosis, respectively, which was significantly inhibited by RSV supplementation. RSV notably activated SIRT1 expression and decreased the expression levels of ATF6, Fsp27β/CIDEC, CREBH, and PLIN1, which are associated with LD accumulation. Interestingly, the inhibitory effects of RSV on LD accumulation and the associated expression of genes in hepatocytes were abrogated or strengthened with SIRT1 silencing or overexpression, respectively. On the contrary, the benefits of RSV in hepatocytes were eliminated or aggravated when transfected with the overexpressed ATF6 or ATF6 siRNA, respectively. Furthermore, we found that RSV stimulated SIRT1 expression significantly, which was followed by increased deacetylation and inactivation of ATF6, resulting in a positive feedback loop for SIRT1 transcription associated with ATF6 binding to the SIRT1 promoter region. Conclusion: Taken together, these findings indicate that RSV supplementation improves hepatic steatosis by ameliorating the accumulation of LDs, and this might be partially mediated by a SIRT1/ATF6-dependent mechanism.

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“…Two animal studies in cholestatic and nonalcoholic fatty liver disease seem in favor of a protective effect of TLR7 against disease progression and fibrosis . Expression of TLRs, including TLR7, was also elevated in a chronic ethanol‐feeding model.…”

Section: Discussionmentioning

confidence: 98%

Deficient IL‐6/Stat3 Signaling, High TLR7, and Type I Interferons in Early Human Alcoholic Liver Disease: A Triad for Liver Damage and Fibrosis

et al. 2019

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Mechanisms underlying alcohol‐induced liver injury and its progression still remain incompletely understood. Animal models can only address some aspects of the pathophysiology that requires studies directly in humans, which are scarce. We assessed liver inflammatory and immune responses at early stages of alcoholic liver disease in a unique cohort of alcohol‐dependent patients undergoing a highly standardized alcohol withdrawal program. In active drinkers, quantitative real‐time polymerase chain reaction revealed alcohol‐induced activation of tumor necrosis factor alpha, interleukin (IL)‐1β, and nuclear factor kappa B in liver tissue already at early disease stages. Double immunofluorescence staining indicated that this proinflammatory response was restricted to activated, CD68‐positive macrophages. In parallel, down‐regulation of IL‐6, inhibition of the signal transducer and activator of transcription 3 (Stat3) pathway, as well as blunted cyclin D expression in hepatocytes, reduced proliferation and favored hepatocyte apoptosis. In addition, immunofluorescence and quantitative real‐time polymerase chain reaction of liver tissue showed that alcohol also activated the toll‐like receptor (TLR) 7–interferon (IFN) axis in hepatocytes, which was confirmed in alcohol‐stimulated primary human hepatocytes and precision‐cut liver slices in vitro . Activation of the TLR7–IFN axis strongly correlated with liver fibrosis markers and disease progression. Two weeks of abstinence attenuated the inflammatory response but did not allow recovery of the defective Stat3 pathway or effect on fibrosis‐associated factors. Conclusion : In humans, inflammation, activation of the TLR7–IFN axis, and inhibition of Stat3‐dependent repair mechanisms in early alcoholic liver disease pave the way for fibrosis development and ultimately disease progression.

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Toll-like receptor 7 affects the pathogenesis of non-alcoholic fatty liver disease

Cited by 35 publications

References 50 publications

TLR7‐let‐7 Signaling Contributes to Ethanol‐Induced Hepatic Inflammatory Response in Mice and in Alcoholic Hepatitis

TLR7‐let‐7 Signaling Contributes to Ethanol‐Induced Hepatic Inflammatory Response in Mice and in Alcoholic Hepatitis

Resveratrol Ameliorates Lipid Droplet Accumulation in Liver Through a SIRT1/ ATF6-Dependent Mechanism

Deficient IL‐6/Stat3 Signaling, High TLR7, and Type I Interferons in Early Human Alcoholic Liver Disease: A Triad for Liver Damage and Fibrosis

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