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- Title
DGAT1 and DGAT2 Inhibitors for Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) Management: Benefits for Their Single or Combined Application.
- Authors
Longo, Miriam; Paolini, Erika; Di Benedetto, Pietro; Tomassini, Elena; Meroni, Marica; Dongiovanni, Paola
- Abstract
Inhibiting diacylglycerol acetyltransferase (DGAT1, DGAT2) enzymes (iDGAT1, iDGAT2), involved in triglyceride (TG) synthesis, improves hepatic steatosis in metabolic dysfunction-associated steatotic liver disease (MASLD) patients. However, their potential synergism in disease onset (SLD) and progression (metabolic dysfunction-associated steatohepatitis, fibrosis) has been poorly explored. We investigated iDGAT1 and iDGAT2 efficacy, alone or combined (iDGAT1/2) on fat accumulation and hepatocellular injury in hepatocytes (HepG2) and on fibrogenic processes in hepatic stellate cells (LX2). We further tested whether the addition of MitoQ antioxidant to iDGAT1/2 would enhance their effects. SLD and MASH conditions were reproduced in vitro by supplementing Dulbecco's Modified Eagle's Medium (DMEM) with palmitic/oleic acids (PAOA) alone (SLD-medium), or plus Lipopolisaccaride (LPS), fructose, and glucose (MASH-medium). In SLD-medium, iDGAT1 and iDGAT2 individually, and even more in combination, reduced TG synthesis in HepG2 cells. Markers of hepatocellular damage were slightly decreased after single iDGAT exposure. Conversely, iDGAT1/2 counteracted ER/oxidative stress and inflammation and enhanced mitochondrial Tricarboxylic acid cycle (TCA) and respiration. In HepG2 cells under a MASH-like condition, only iDGAT1/2 effectively ameliorated TG content and oxidative and inflammatory mediators, further improving bioenergetic balance. LX2 cells, challenged with SLD/MASH media, showed less proliferation and slower migration rates in response to iDGAT1/2 drugs. MitoQ combined with iDGAT1/2 improved cell viability and dampened free fatty acid release by stimulating β-oxidation. Dual DGAT inhibition combined with antioxidants open new perspectives for MASLD management.
- Subjects
KREBS cycle; INFLAMMATORY mediators; FREE fatty acids; FATTY liver; LIVER cells
- Publication
International Journal of Molecular Sciences, 2024, Vol 25, Issue 16, p9074
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms25169074