Research Article Details

Article ID: A20171
PMID: 26113297
Source: Am J Physiol Gastrointest Liver Physiol
Title: Hepatic TLR4 signaling in obese NAFLD.
Abstract: Nonalcoholic fatty liver disease occurs frequently in the setting of metabolic syndrome, but the factors leading to nonalcoholic steatohepatitis (NASH) are not fully understood. This study investigated Toll-like receptor 4 (TLR4) signaling in human liver with the goal of delineating whether activation of this pathway segregates those with nonalcoholic fatty liver from those with NASH. Experiments were performed using liver biopsy tissue obtained from class III obese subjects undergoing bariatric surgery, and extended to an immortalized human hepatocyte HepaRG cell line and primary human hepatocytes. The bacterial endotoxin lipopolysaccharide (LPS) and total free fatty acid levels were significantly increased in plasma of NASH patients. TLR4 mRNA levels were significantly increased in subjects with NASH compared with NAFL as was interferon regulatory factor (IRF) 3 in the myeloid differentiation factor 88-independent signaling pathway. In HepaRG cells, nuclear factor-κB (NF-κB) nuclear translocation and functional activity increased following treatment with the fatty acid, palmitate, and following exposure to LPS compared with hepatocytes stimulated with a lipogenic treatment that induced de novo lipogenesis. Palmitate and LPS induction of NF-κB activity was partially attenuated by chemical- or small-interfering RNA-mediated inhibition of TLR4. Expression of TLR4 and its downstream mediators was upregulated with palmitate and LPS. Similar results were observed using primary human hepatocytes from a lean donor. Interestingly, NF-κB activity assays showed obese donor hepatocytes were resistant to chemical TLR4 inhibition. In conclusion, TLR4 expression is upregulated in a large cohort of NASH patients, compared with those with NAFL, and this occurs within the setting of increased LPS and fatty acids.
DOI: 10.1152/ajpgi.00304.2014

Strategy ID Therapy Strategy Synonyms Therapy Targets Therapy Drugs
S09 Bariatric surgery Metabolic surgery -- -- Details
S07 Anti-lipogenesis de novo lipogenesis; de novo lipogenesis; DNL; anti-lipogenic mechanisms; adipogenesis; anti-obesity stearoyl-CoA desaturase 1 (SCD-1); Acetyl-coenzyme carboxylase; acyl-CoA carboxylase inhibitor (ACC inhibitor); stearoyl Coenzyme A desaturase inhibitor (SCD inhibitor); THR-beta selective agonist; DGAT2 inhibitor; FASN inhibitor Aramchol; Firsocostat (GS-0976); VK-2809; ION 224 Details

Target ID Target Name GENE Action Class UniProtKB ID Entry Name
T09 Toll-like receptor 4 TLR4 antagonist Membrane receptor O00206 TLR4_HUMAN Details
T18 Acetyl-CoA carboxylase 1 ACACA inhibitor Enzyme Q13085 ACACA_HUMAN Details
T07 Bile acid receptor NR1H4 agonist Nuclear hormone receptor Q96RI1 NR1H4_HUMAN Details

Diseases ID DO ID Disease Name Definition Class
I14 9970 Obesity An overnutrition that is characterized by excess body fat, traditionally defined as an elevated ratio of weight to height (specifically 30 kilograms per meter squared), has_material_basis_in a multifactorial etiology related to excess nutrition intake, decreased caloric utilization, and genetic susceptibility, and possibly medications and certain disorders of metabolism, endocrine function, and mental illness. https://en.wikipedia.org/wiki/Obesity disease of metabolism/acquired metabolic disease/ nutrition disease/overnutrition Details

Drug ID Drug Name Type DrugBank ID Targets Category Latest Progress
D248 Obeticholic Acid Chemical drug DB05990 NR1H4 activator; NR1H4 agonist; FXR agonist Enhance lipid metabolism Approval rejected Details
D328 Serine Chemical drug DB00133 SRR Improve insulin resistance Under clinical trials Details
D083 CLA Chemical drug DB01211 KCNH2; SLCO1B1; SLCO1B3 -- Under clinical trials Details