Impaired glycosylation promotes rapid transition to hepatocellular carcinoma in model of diet-induced steatotic liver disease
Abhishek K. Singh, Balkrishna Chaube, Kathryn M. Citrin, Joseph W.M. Fowler, Sungwoon Lee, Jonatas Catarino, James Knight, Sarah C. Lowery, Sonal Shree, Keira E. Mahoney, Nabil E. Boutagy, Inmaculada Ruz-Maldonado, Kathy Harry, Marya Shanabrough, Trenton T. Ross, Stacy A. Malaker, Yajaira Suárez, Carlos Fernández-Hernando, Kariona A. Grabińska, William C. Sessa
Abhishek K. Singh, Balkrishna Chaube, Kathryn M. Citrin, Joseph W.M. Fowler, Sungwoon Lee, Jonatas Catarino, James Knight, Sarah C. Lowery, Sonal Shree, Keira E. Mahoney, Nabil E. Boutagy, Inmaculada Ruz-Maldonado, Kathy Harry, Marya Shanabrough, Trenton T. Ross, Stacy A. Malaker, Yajaira Suárez, Carlos Fernández-Hernando, Kariona A. Grabińska, William C. Sessa
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Research Article Hepatology Metabolism Oncology

Impaired glycosylation promotes rapid transition to hepatocellular carcinoma in model of diet-induced steatotic liver disease

Abstract

Obesity-linked steatosis is a significant risk factor for hepatocellular carcinoma (HCC); however, the molecular mechanisms underlying the transition from metabolic dysfunction–associated steatotic liver disease (MASLD) to HCC remain unclear. Here, we explored the role of the ER-associated protein NgBR, an essential component of the cis-prenyltransferase (cis-PTase) enzyme, in chronic liver disease. Hepatocyte-specific NgBR deletion in mice (N-LKO) intensified triacylglycerol (TAG) accumulation, inflammatory responses, ER/oxidative stress, and fibrosis, ultimately resulting in HCC development with 100% penetrance after 4 months on a high-fat diet. Similarly, liver-specific knockout of DHDDS, NgBR’s cis-PTase partner, and a knockin model carrying a human NgBR mutation that impairs cis-PTase activity developed HCC under high-fat diet conditions, although with lower penetrance. A single-cell transcriptomic atlas from affected livers provides a detailed molecular analysis of the transition from liver pathophysiology to HCC development. Mechanistically, NgBR deficiency promoted excessive hepatic TAG accumulation by enhancing lipid uptake and impairing VLDL secretion. Importantly, pharmacological inhibition of diacylglycerol acyltransferase-2 (DGAT2), a key enzyme in TAG synthesis, abrogated diet-induced liver damage and HCC burden in N-LKO mice. Overall, our findings establish cis-PTase as a critical suppressor of MASLD-HCC conversion and suggest DGAT2 inhibition may serve as a promising therapeutic approach to delay HCC formation in advanced metabolic dysfunction–associated steatohepatitis.

Authors

Abhishek K. Singh, Balkrishna Chaube, Kathryn M. Citrin, Joseph W.M. Fowler, Sungwoon Lee, Jonatas Catarino, James Knight, Sarah C. Lowery, Sonal Shree, Keira E. Mahoney, Nabil E. Boutagy, Inmaculada Ruz-Maldonado, Kathy Harry, Marya Shanabrough, Trenton T. Ross, Stacy A. Malaker, Yajaira Suárez, Carlos Fernández-Hernando, Kariona A. Grabińska, William C. Sessa

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Figure 5

DGAT2 inhibitor treatment prevents diet-induced MASLD-HCC pathogenesis.

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DGAT2 inhibitor treatment prevents diet-induced MASLD-HCC pathogenesis. ...
This study involved 3 groups of mice: WT mice on a WD for 16 weeks, and N-LKO mice divided into 2 subgroups — 1 on WD only and the other on WD with a DGAT2 inhibitor (N-LKO+DGI) for 16 weeks. After 16 weeks, the following parameters were measured. (A) Hepatic TAG levels (n = 5). (B) Representative images and quantification of Sirius red and trichrome staining in liver sections (n = 5). Original magnification, x20. (C and D) Serum ALT and AST levels (WT, n = 5; N-LKO, n = 6; N-LKO+DGI, n = 7). (E) Analysis of cellular ROS in primary hepatocytes (n = 3). (F) Membrane lipid peroxidation via MDA assay in the liver (n = 4). (G) Western blot and densitometric analysis of ER stress proteins ATF4 and HSP90 (n = 3). (H and I) Photographs of livers from N-LKO and N-LKO+DGI mice, with H&E-stained liver and tumor sections, and a graph summarizing tumor occurrence (n = 8). Original magnification, x5. (J) Plasma AFP levels (WT, n = 5; N-LKO, n = 8; N-LKO+DGI, n = 8). Data are presented as mean ± SEM, with each point representing a biological sample. Statistical analysis: 1-way ANOVA with Tukey’s test (*P < 0.05, **P < 0.01, and ***P < 0.001). (K) Proposed mechanism illustrating the role of liver-derived NgBR in hepatic lipid metabolism.