Research Article Details
| Article ID: | A23313 |
| PMID: | 23855299 |
| Source: | J Gastroenterol Hepatol |
| Title: | Non-alcoholic steatohepatitis: pathogenesis and novel therapeutic approaches. |
| Abstract: | Non-alcoholic fatty liver disease (NAFLD) refers to a disease spectrum, ranging from mere hepatic steatosis to hepatic necroinflammation (NASH, non-alcoholic steatohepatitis). NASH often leads to fibrosis, which can progress to cirrhosis with a high risk of liver failure and hepatocellular carcinoma. The course of NAFLD is highly variable, and only a minority of patients (2-3%) progress to end-stage liver disease. However, due to a dramatic increase of the risk factors for NAFLD, that is obesity and insulin resistance/type 2 diabetes, that affect 15-30% and 7-15% of subjects, in most industrialized countries, respectively, NAFLD has become the most frequent liver disease and is even considered a pace setter of the metabolic syndrome. Sedentary lifestyle, modern Western nutrition, and genetic predispositions have been identified as major causes of NAFLD. These lead to liver injury via insulin resistance and an excess of free fatty acids in hepatocytes, resulting in oxidant stress and lipotoxicity that promote the activation of intracellular stress kinases and apoptosis or necroapoptosis (NASH). The damaged hepatocytes directly trigger inflammation and fibrogenesis, but can also lead to the emergence of fibrogenic progenitor cells. Moreover, NASH is linked to inflammation in peripheral adipose tissues that involves mainly macrophages and humoral factors, such as adipokines and cytokines. The most efficient treatment is by weight loss and exercise, but (adjunctive) pharmacological strategies are urgently needed. Here, we highlight the aspects of NAFLD epidemiology and pathophysiology that are beginning to lead to novel pharmacological approaches to address this growing health-care challenge. |
| DOI: | 10.1111/jgh.12212 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S01 | Improve insulin resistance | insulin sensitizer; insulin resistance; glucose tolerance | Biguanide: increases 5-AMP activated protein kinase signaling; SGLT-2 inhibitor; Thiazalidinedione: selective PPAR-γ agonists; GLP-1 agonist | Metformin; Empagliflozin; Canagliflozin; Rosiglitazone; Pioglitazone; Liraglutide | 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 |
| S04 | Anti-oxidative stress | oxidative stress | α-tocopherol: antioxidant | Vitamin E | Details |
| S08 | Lifestyle measures | Lifestyle intervention; weight loss; diet adaptation; dietary interventions; lifestyle modifications; Exercise | -- | -- | 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 | |
|---|---|---|---|---|---|---|---|
| T17 | Farnesoid X-activated receptor | NR1H4 | agonist | Nuclear hormone receptor | Q96RI1 | NR1H4_HUMAN | Details |
| T06 | Glucagon-like peptide 1 receptor | GLP1R | agonist | GPCR | P43220 | GLP1R_HUMAN | Details |
| T07 | Bile acid receptor | NR1H4 | agonist | Nuclear hormone receptor | Q96RI1 | NR1H4_HUMAN | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I05 | 9352 | Type 2 diabetes mellitus | A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 | disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus | Details |
| 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 | |
|---|---|---|---|---|---|---|---|
| D080 | Citrulline | Chemical drug | DB00155 | -- | -- | Under clinical trials | Details |
| D579 | Emfilermin | Miscellany | -- | adipocytes | Enhance lipid metabolism | Under investigation | Details |
| D284 | Probiotic | Supplement | -- | -- | -- | Under clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |