Liver ASK1 protects from non‐alcoholic fatty liver disease and fibrosis
Abstract Non‐alcoholic fatty liver disease (NAFLD) is strongly associated with obesity and may progress to non‐alcoholic steatohepatitis (NASH) and liver fibrosis. The deficit of pharmacological therapies for the latter mainly results from an incomplete understanding of involved pathological mechani...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2019-06-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201810124 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850204030484086784 |
|---|---|
| author | Tenagne D Challa Stephan Wueest Fabrizio C Lucchini Mara Dedual Salvatore Modica Marcela Borsigova Christian Wolfrum Matthias Blüher Daniel Konrad |
| author_facet | Tenagne D Challa Stephan Wueest Fabrizio C Lucchini Mara Dedual Salvatore Modica Marcela Borsigova Christian Wolfrum Matthias Blüher Daniel Konrad |
| author_sort | Tenagne D Challa |
| collection | DOAJ |
| description | Abstract Non‐alcoholic fatty liver disease (NAFLD) is strongly associated with obesity and may progress to non‐alcoholic steatohepatitis (NASH) and liver fibrosis. The deficit of pharmacological therapies for the latter mainly results from an incomplete understanding of involved pathological mechanisms. Herein, we identify apoptosis signal‐regulating kinase 1 (ASK1) as a suppressor of NASH and fibrosis formation. High‐fat diet‐fed and aged chow‐fed liver‐specific ASK1‐knockout mice develop a higher degree of hepatic steatosis, inflammation, and fibrosis compared to controls. In addition, pharmacological inhibition of ASK1 increased hepatic lipid accumulation in wild‐type mice. In line, liver‐specific ASK1 overexpression protected mice from the development of high‐fat diet‐induced hepatic steatosis and carbon tetrachloride‐induced fibrosis. Mechanistically, ASK1 depletion blunts autophagy, thereby enhancing lipid droplet accumulation and liver fibrosis. In human livers of lean and obese subjects, ASK1 expression correlated negatively with liver fat content and NASH scores, but positively with markers for autophagy. Taken together, ASK1 may be a novel therapeutic target to tackle NAFLD and liver fibrosis. |
| format | Article |
| id | doaj-art-e34078afbfda453eaefc34f8adc5adcd |
| institution | OA Journals |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2019-06-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-e34078afbfda453eaefc34f8adc5adcd2025-08-20T02:11:22ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842019-06-01111011710.15252/emmm.201810124Liver ASK1 protects from non‐alcoholic fatty liver disease and fibrosisTenagne D Challa0Stephan Wueest1Fabrizio C Lucchini2Mara Dedual3Salvatore Modica4Marcela Borsigova5Christian Wolfrum6Matthias Blüher7Daniel Konrad8Division of Pediatric Endocrinology and Diabetology, University Children's HospitalDivision of Pediatric Endocrinology and Diabetology, University Children's HospitalDivision of Pediatric Endocrinology and Diabetology, University Children's HospitalDivision of Pediatric Endocrinology and Diabetology, University Children's HospitalInstitute of Food, Nutrition and Health, ETH ZurichDivision of Pediatric Endocrinology and Diabetology, University Children's HospitalInstitute of Food, Nutrition and Health, ETH ZurichDepartment of Medicine, University of LeipzigDivision of Pediatric Endocrinology and Diabetology, University Children's HospitalAbstract Non‐alcoholic fatty liver disease (NAFLD) is strongly associated with obesity and may progress to non‐alcoholic steatohepatitis (NASH) and liver fibrosis. The deficit of pharmacological therapies for the latter mainly results from an incomplete understanding of involved pathological mechanisms. Herein, we identify apoptosis signal‐regulating kinase 1 (ASK1) as a suppressor of NASH and fibrosis formation. High‐fat diet‐fed and aged chow‐fed liver‐specific ASK1‐knockout mice develop a higher degree of hepatic steatosis, inflammation, and fibrosis compared to controls. In addition, pharmacological inhibition of ASK1 increased hepatic lipid accumulation in wild‐type mice. In line, liver‐specific ASK1 overexpression protected mice from the development of high‐fat diet‐induced hepatic steatosis and carbon tetrachloride‐induced fibrosis. Mechanistically, ASK1 depletion blunts autophagy, thereby enhancing lipid droplet accumulation and liver fibrosis. In human livers of lean and obese subjects, ASK1 expression correlated negatively with liver fat content and NASH scores, but positively with markers for autophagy. Taken together, ASK1 may be a novel therapeutic target to tackle NAFLD and liver fibrosis.https://doi.org/10.15252/emmm.201810124autophagyhigh‐fat dietNASH |
| spellingShingle | Tenagne D Challa Stephan Wueest Fabrizio C Lucchini Mara Dedual Salvatore Modica Marcela Borsigova Christian Wolfrum Matthias Blüher Daniel Konrad Liver ASK1 protects from non‐alcoholic fatty liver disease and fibrosis EMBO Molecular Medicine autophagy high‐fat diet NASH |
| title | Liver ASK1 protects from non‐alcoholic fatty liver disease and fibrosis |
| title_full | Liver ASK1 protects from non‐alcoholic fatty liver disease and fibrosis |
| title_fullStr | Liver ASK1 protects from non‐alcoholic fatty liver disease and fibrosis |
| title_full_unstemmed | Liver ASK1 protects from non‐alcoholic fatty liver disease and fibrosis |
| title_short | Liver ASK1 protects from non‐alcoholic fatty liver disease and fibrosis |
| title_sort | liver ask1 protects from non alcoholic fatty liver disease and fibrosis |
| topic | autophagy high‐fat diet NASH |
| url | https://doi.org/10.15252/emmm.201810124 |
| work_keys_str_mv | AT tenagnedchalla liverask1protectsfromnonalcoholicfattyliverdiseaseandfibrosis AT stephanwueest liverask1protectsfromnonalcoholicfattyliverdiseaseandfibrosis AT fabrizioclucchini liverask1protectsfromnonalcoholicfattyliverdiseaseandfibrosis AT maradedual liverask1protectsfromnonalcoholicfattyliverdiseaseandfibrosis AT salvatoremodica liverask1protectsfromnonalcoholicfattyliverdiseaseandfibrosis AT marcelaborsigova liverask1protectsfromnonalcoholicfattyliverdiseaseandfibrosis AT christianwolfrum liverask1protectsfromnonalcoholicfattyliverdiseaseandfibrosis AT matthiasbluher liverask1protectsfromnonalcoholicfattyliverdiseaseandfibrosis AT danielkonrad liverask1protectsfromnonalcoholicfattyliverdiseaseandfibrosis |