Research Article Details
| Article ID: | A25473 |
| PMID: | 21794038 |
| Source: | Hepatol Res |
| Title: | Weight loss amelioration of non-alcoholic steatohepatitis linked to shifts in hepatic ceramide expression and serum ceramide levels. |
| Abstract: | AIM:   Non-alcoholic steatohepatitis (NASH) is associated with increased hepatic insulin resistance. Ceramides and other toxic sphingolipids promote inflammation, lipotoxicity and insulin resistance; however, the role of ceramides in the pathogenesis of NASH has not been determined. This study characterizes expression of ceramide-related genes in human livers with NASH and examines the effects of weight loss on NASH and pro-ceramide gene expression in liver. METHODS:   Liver biopsies were obtained to assess the histopathological status of non-alcoholic fatty liver disease/NASH prior to and following completion of a 1-year course of implementing either lifestyle changes or a standard enrichment protocol designed to encourage weight loss. Liver biopsy samples were used to measure pro-ceramide gene expression by quantitative reverse transcriptase polymerase chain reaction analysis (qRT-PCR), and serum was used to measure ceramide immunoreactivity. RESULTS:   At baseline, serine palmitoyltransferase (SPTLC)2 (P = 0.02) and ceramide synthase (CER)1 (P = 0.001) mRNA transcripts were less abundantly expressed in livers with NASH relative to normal controls. After weight loss (average 9.3%), SPTLC1 (P = 0.005) and uridine diphosphate glucose ceramide glucosyltransferase (UGCG) (P = 0.001) expression significantly declined while CER1 increased (P = 0.001) among subjects randomized to the lifestyle change subgroup. Reductions in calorie and fat consumption were significantly correlated with changes in ceramide-related gene expression. Finally, both net and relative reductions in serum ceramide levels were significantly greater in the lifestyles compared with the standard enrichment (control) protocol group (both P < 0.005). CONCLUSION:   NASH is associated with increased insulin resistance and altered ceramide gene expression in liver. Weight loss-mediated reversal of NASH is associated with reduced pro-ceramide gene expression in liver. |
| DOI: | 10.1111/j.1872-034X.2011.00815.x |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S08 | Lifestyle measures | Lifestyle intervention; weight loss; diet adaptation; dietary interventions; lifestyle modifications; Exercise | -- | -- | Details |
| 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 |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name |
|---|
| 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 |
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D579 | Emfilermin | Miscellany | -- | adipocytes | Enhance lipid metabolism | Under investigation | Details |
| D328 | Serine | Chemical drug | DB00133 | SRR | Improve insulin resistance | Under clinical trials | Details |
| D080 | Citrulline | Chemical drug | DB00155 | -- | -- | Under clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |
| D316 | S-adenosyl-L-methionine | Chemical drug | DB00118 | GNMT cofactor | Antiviral | 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 |