Research Article Details
| Article ID: | A35659 |
| PMID: | 19998387 |
| Source: | Hepatology |
| Title: | Major histocompatibility complex class I-related chains A and B (MIC A/B): a novel role in nonalcoholic steatohepatitis. |
| Abstract: | UNLABELLED: Stress-induced soluble major histocompatibility complex class I-related chains A/B (MIC A/B) are increased in chronic liver diseases and hepatocellular malignancy. We investigated the impact of these molecules on liver injury, apoptosis, and fibrosis in nonalcoholic steatohepatitis (NASH). Blood and liver tissue were obtained from 40 patients with NASH undergoing bariatric surgery for obesity. The control group consisted of 10 healthy individuals. We also investigated 10 patients with nonalcoholic fatty liver (NAFL). Polymerase chain reaction was used to measure messenger RNA (mRNA) transcripts of MIC A/B, natural killer cell receptor G2D (NKG2D), CD95/Fas, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-death receptor 5 (DR5). Apoptosis was quantified by way of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) (intrahepatic) and M30/M65 (systemic). Liver injury was assessed histopathologically and serologically (alanine aminotransferase/aspartate aminotransferase). Fibrosis was identified by Sirius red staining, quantitative morphometry, and alpha-smooth muscle actin and collagen 1alpha transcripts. Compared with controls, patients with NASH revealed significant increases in (1) NKG2D mRNA (13.1-fold) and MIC A/B mRNA (3.6-fold and 15.8-fold, respectively); (2) TRAIL-DR5 and CD95/Fas mRNA (2.7-fold and 3.6-fold, respectively); (3) TUNEL-positive hepatocytes (4.0-fold); and (4) M30 and M65 levels (4.6-fold and 3.4-fold, respectively). We found relevant correlations between MIC protein expression rates and NAS and fibrosis stages. In contrast, NKG2D and MIC A/B transcripts were attenuated in patients with NAFL compared with NASH. Histopathologically, NASH patients revealed increased NAS scores, an accumulation of natural killer cells, and 2.7-fold increased hepatic fibrosis by quantitative morphometry. CONCLUSION: Our findings suggest an important role for MIC A/B in liver injury. Therapeutic intervention aimed at reducing MIC A/B levels may beneficially affect the progression of NASH. |
| DOI: | 10.1002/hep.23253 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S09 | Bariatric surgery | Metabolic surgery | -- | -- | Details |
| S03 | Anti-fibrosis | fibrosis | Angiotensin Receptor Blocker (ARB); CCR2/CCR5 antagonist; Thyroid receptor β agonist; PEGylated human FGF21 analogue; Monoclonal antibody to lysyl oxidase-like 2 (LOXL2); Galectin-3 inhibitor; FGF19 variant | Losartan; Cenicriviroc; VK-2809; MGL-3196; Pegbelfermin; Simtuzumab; GR-MD-02; NGM282 | Details |
| S13 | Anti-apoptosis | hepatocyte apoptosis; hepatic autophagy; apoptosis | Pan-caspase inhibitor | Emricasan | Details |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name | |
|---|---|---|---|---|---|---|---|
| T08 | Tumor necrosis factor | TNF | inhibitor | Cytokine | P01375 | TNFA_HUMAN | Details |
| T18 | Acetyl-CoA carboxylase 1 | ACACA | inhibitor | Enzyme | Q13085 | ACACA_HUMAN | Details |
| T20 | Fatty acid synthase | FASN | inhibitor | Enzyme | P49327 | FAS_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 | |
|---|---|---|---|---|---|---|---|
| D199 | L-alanine | Chemical drug | DB00160 | KYNU | -- | Failed in clinical trials | 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 |
| D094 | Cysteamine | Chemical drug | DB00847 | GSS stimulant | Renal drug | Under clinical trials | Details |
| D095 | Cysteamine bitartrate | Chemical drug | DB00847 | -- | -- | Under clinical trials | Details |