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 4

Loss of NgBR function in the liver enhances lipid uptake and impairs VLDL-TAG secretion.

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Loss of NgBR function in the liver enhances lipid uptake and impairs VLD...
(A) Circulating TAG levels in overnight-fasted WT and N-LKO mice on a 6-month CD (n = 6). (B) TAG content of FPLC-fractionated lipoproteins from pooled plasma of overnight-fasted WT and N-LKO mice fed a CD for 6 months (n = 5). (C) Western blot analyses of plasma ApoB100 and ApoB48 in the VLDL fractions from FPLC-fractionated lipoproteins (n = 5). (D) Oral lipid tolerance test: TAG clearance from the plasma of WT and N-LKO mice, fasted for 4 hours, then given an oral gavage of olive oil (n = 5). (E) Radiolabeled triolein uptake in various tissues 2 hours after oral gavage in WT and N-LKO mice fasted for 6 hours (n = 3–4). BAT, brown adipose tissue; WAT, white adipose tissue. (F) Plasma TAG levels in overnight-fasted WT and N-LKO mice treated with lipoprotein lipase inhibitor 407 to block lipolysis of circulating TAG-rich lipoprotein (n = 5). (G) Representative images of H&E-stained and Oil Red O–stained liver sections. Original magnification, x40. (H) Hepatic TAG levels in WT and N-LKO mice fed a CD for 6 months (n = 4). Statistical analysis: **P < 0.01 and ***P < 0.001 using a 2-sided Welch’s t test (A, E, and H) and ***P < 0.001 using 2-way ANOVA with Šidák’s multiple-comparison test (F).