Impaired glycosylation promotes rapid transition to hepatocellular carcinoma in model of diet induced steatotic liver disease - PubMed
3 days ago
- #DGAT2 inhibition
- #Metabolic dysfunction-associated steatotic liver disease
- #Hepatocellular carcinoma
- Obesity-linked steatosis is a significant risk factor for hepatocellular carcinoma (HCC).
- Hepatocyte-specific NgBR deletion in mice (N-LKO) leads to increased triacylglycerol (TAG) accumulation, inflammation, ER/oxidative stress, fibrosis, and HCC development with 100% penetrance after four months on a high-fat diet.
- Liver-specific knockout of DHDDS (D-LKO) and a knock-in model with a human NgBR mutation impairing cis-PTase activity also developed HCC under high-fat diet conditions, but with lower penetrance.
- NgBR deficiency promotes excessive hepatic TAG accumulation by enhancing lipid uptake and impairing VLDL secretion.
- Pharmacological inhibition of DGAT2, a key enzyme in TAG synthesis, prevents diet-induced liver damage and HCC burden in N-LKO mice.
- cis-PTase is identified as a critical suppressor of MASLD-HCC conversion, and DGAT2 inhibition is suggested as a potential therapeutic approach to delay HCC formation in advanced MASH.