| RRC ID |
83361
|
| Author |
Etemad A, Tanaka Y, Wang S, Slae M, Sultan M, Elpeleg O, Hirokawa N.
|
| Title |
Mutations in the kinesin KIF12 promote MASH in humans and mice by disrupting lipogenic enzyme turnover.
|
| Journal |
EMBO J
|
| Abstract |
As a common cause of liver cirrhosis, metabolic dysfunction-associated steatohepatitis (MASH) is regarded as a target of therapeutic intervention. However, a successful therapy has not yet been found, partly because the molecular pathogenesis is largely elusive. Here we show that KIF12 kinesin suppresses MASH development by accelerating the breakdown of two lipid biosynthesis enzymes, acetyl-CoA carboxylase 1 (ACC1) and pyruvate carboxylase (PC), in hepatocytes. We report three familial early-onset liver cirrhosis pedigrees with homozygous KIF12 mutations, accompanying MASH-like steatosis and cholestasis. The mouse genetic model carrying the corresponding Kif12 nonsense mutation faithfully reproduced the phenotypes as early as between 8 and 10 weeks of age. Furthermore, KIF12-deficient HepG2 cells exhibited significant steatosis, which was ameliorated by overexpressing a proline-rich domain (PRD) of KIF12. We found that KIF12-PRD promotes the degradation of ACC1 and PC, and this effect is likely to be through its direct interaction with these enzymes. Interestingly, KIF12 enhanced the ubiquitination of ACC1 by the E3 ligase COP1 and colocalized with these proteins as seen by super-resolution microscopy imaging. These data propose a role for KIF12 in suppressing MASH by accelerating turnover of lipogenic enzymes.
|
| Volume |
44(6)
|
| Pages |
1608-1640
|
| Published |
2025-3-1
|
| DOI |
10.1038/s44318-025-00366-8
|
| PII |
10.1038/s44318-025-00366-8
|
| PMID |
39920308
|
| PMC |
PMC11914266
|
| MeSH |
Acetyl-CoA Carboxylase* / genetics
Acetyl-CoA Carboxylase* / metabolism
Animals
Disease Models, Animal
Female
Hep G2 Cells
Hepatocytes / metabolism
Humans
Kinesins* / genetics
Kinesins* / metabolism
Lipogenesis*
Liver Cirrhosis* / genetics
Liver Cirrhosis* / metabolism
Liver Cirrhosis* / pathology
Male
Mice
Mutation
Pedigree
|
| IF |
9.889
|
| Resource |
| Human and Animal Cells |
Hep G2 |
