RT Journal Article
SR Electronic
T1 Hepatocyte-specific miR-33 deletion attenuates NAFLD-NASH-HCC progression
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2023.01.18.523503
DO 10.1101/2023.01.18.523503
A1 Pablo Fernández-Tussy
A1 Jonathan Sun
A1 Magdalena P. Cardelo
A1 Nathan L. Price
A1 Leigh Goedeke
A1 Chrysovalantou E. Xirouchaki
A1 Xiaoyong Yang
A1 Oscar Pastor-Rojo
A1 Anton M. Bennett
A1 Tony Tiganis
A1 Yajaira Suárez
A1 Carlos Fernández-Hernando
YR 2023
UL http://biorxiv.org/content/early/2023/01/20/2023.01.18.523503.abstract
AB The complexity of the multiple mechanisms underlying non-alcoholic fatty liver disease (NAFLD) progression remains a significant challenge for the development of effective therapeutics. miRNAs have shown great promise as regulators of biological processes and as therapeutic targets for complex diseases. Here, we study the role of hepatic miR-33, an important regulator of lipid metabolism, during the progression of NAFLD. We report that miR-33 is overexpressed in hepatocytes isolated from mice with NAFLD and demonstrate that its specific suppression in hepatocytes (miR-33 HKO) improves multiple aspects of the disease, including insulin resistance, steatosis, and inflammation and limits the progression to non-alcoholic steatohepatitis (NASH), fibrosis and hepatocellular carcinoma (HCC). Mechanistically, we find that hepatic miR-33 deficiency reduces lipid biosynthesis and promotes mitochondrial fatty acid oxidation to reduce lipid burden in hepatocytes. Additionally, miR-33 deficiency improves mitochondrial function, reducing oxidative stress. In miR-33 deficient hepatocytes, we found an increase in AMPKα activation, which regulates several pathways resulting in the attenuation of liver disease. The reduction in lipid accumulation and liver injury resulted in decreased transcriptional activity of the YAP/TAZ pathway, which may be involved in the reduced progression to HCC in the HKO livers. Together, these results suggest suppressing hepatic miR-33 may be an effective therapeutic approach at different stages of NAFLD/NASH/HCC disease progression.Competing Interest StatementThe authors have declared no competing interest.