Lipid balance must be just right to prevent development of severe liver damage
Timothy F. Osborne, Peter J. Espenshade
Timothy F. Osborne, Peter J. Espenshade
Published June 1, 2022
Citation Information: J Clin Invest. 2022;132(11):e160326. https://doi.org/10.1172/JCI160326.
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Commentary

Lipid balance must be just right to prevent development of severe liver damage

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a major health concern that often associates with obesity and diabetes. Fatty liver is usually a benign condition, yet a fraction of individuals progress to severe forms of liver damage, including nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Elevated sterol regulatory element–binding protein–driven (SREBP-driven) hepatocyte lipid synthesis is associated with NAFLD in humans and mice. In this issue of the JCI, Kawamura, Matsushita, et al. evaluated the role of SREBP-dependent lipid synthesis in the development of NAFLD, NASH, and HCC in the phosphatase and tensin homolog–knockout (PTEN-knockout) NASH model. Deletion of the gene encoding SREBP cleavage–activating protein (SCAP) from the liver resulted in decreased hepatic lipids, as expected. However, SCAP deletion accelerated progression to more severe liver damage, including NASH and HCC. This study provides a note of caution for those pursuing de novo fat biosynthesis as a therapeutic intervention in human NASH.

Authors

Timothy F. Osborne, Peter J. Espenshade

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Figure 1

Lipid imbalances in the liver can lead to NASH and HCC progression.

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Lipid imbalances in the liver can lead to NASH and HCC progression. Kawa...
Kawamura, Matsushita, et al. (8) showed that a liver-specific PTEN deficiency resulted in excess lipids and steatosis in mice. Notably, PTEN deficiency in the context of SCAP deficiency, which reduces steatosis, exacerbated the later stage development of inflammation and liver injury and accelerated the development of NASH and HCC.