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Activation of the Hippo pathway effector Yap underlies many liver cancers, however no germline or somatic mutations have been identified. Autophagy maintains essential metabolic functions of the liver, and autophagy-deficient murine models develop benign adenomas and hepatomegaly, which have been attributed to activation of the p62/Sqstm1-Nrf2 axis. Here, we show that Yap is an autophagy substrate and mediator of tissue remodeling and hepatocarcinogenesis independent of the p62/Sqstm1-Nrf2 axis. Hepatocyte-specific deletion of Atg7 promotes liver size, fibrosis, progenitor cell expansion, and hepatocarcinogenesis, which is rescued by concurrent deletion of Yap. Our results shed new light on mechanisms of Yap degradation and the sequence of events that follow disruption of autophagy, which is impaired in chronic liver disease.

Background: Lysosomes are required for autophagic degradation, which can be suppressed by lysosome inhibitors. Results: Inhibition of lysosome function resulted in autophagy activation via down-regulation of MTORC1. Conclusion: Lysosomes can affect autophagy initiation in addition to its role in autophagy degradation. Significance: The finding expands lysosome function to include regulation of autophagy activation and indicates a dual effect of lysosome inhibitors in autophagy.

In our published work, we reported that HMGB1 is actively released from autophagy-deficient hepatocytes via a pathway from NRF2 to inflammasomes to promote ductular reaction, hepatic progenitor cell expansion, and tumorigenesis. We based our conclusions on multiple lines of evidence. Release of HMGB1 from autophagy-deficient hepatocytes was documented by immunoblotting, immunostaining, and ELISA analysis in different age groups of autophagy-deficient mice. The release of HMGB1 through an active mechanism is supported by kinetics analysis that shows tissue injury can be separated from the release process and by pharmacological and genetic analyses showing that the molecular elements of NRF2 and CASPASE 1 are required. The impact of HMGB1 on ductular reaction and tumor progression was also documented by both in vivo and in vitro evidence using knockout mice, cell fractionation, and transcriptional analysis. Figure 1G showed the results of an analysis of HMGB1 isoforms by mass spectrometry that was undertaken in a separate laboratory by Daniel J. Antoine. In February 2019, we learned that these data were likely compromised. We contacted the journal, and the Editorial Board gave us permission to correct the study. In the corrected version, all conclusions based on Figure 1G have been removed, and the journal has published an online version of the original article with the unreliable statements crossed out and the modified text highlighted in red (Supplemental File, Redaction). Figure 1G only suggested the formation of the released HMGB1, but carried no significance as to the releasing mechanisms and the functional significance of HMGB1 release in autophagy-deficient conditions. We thus believe that the major conclusions of the study on the releasing mechanism and functional significance of HMGB1 in autophagy-deficient conditions are independent of Figure 1G and are accurate and that the corrected paper is reliable.

Autophagy is important for liver homeostasis, and the deficiency leads to injury, inflammation, ductular reaction (DR), fibrosis, and tumorigenesis. It is not clear how these events are mechanistically linked to autophagy deficiency. Here, we reveal the role of high-mobility group box 1 (HMGB1) in two of these processes. First, HMGB1 was required for DR, which represents the expansion of hepatic progenitor cells (HPCs) implicated in liver repair and regeneration. DR caused by hepatotoxic diets (3,5-diethoxycarbonyl-1,4-dihydrocollidine [DDC] or choline-deficient, ethionine-supplemented [CDE]) also depended on HMGB1, indicating that HMGB1 may be generally required for DR in various injury scenarios. Second, HMGB1 promoted tumor progression in autophagy-deficient livers. Receptor for advanced glycation end product (RAGE), a receptor for HMGB1, was required in the same two processes and could mediate the proliferative effects of HMBG1 in isolated HPCs. HMGB1 was released from autophagy-deficient hepatocytes independently of cellular injury but depended on NRF2 and the inflammasome, which was activated by NRF2. Pharmacological or genetic activation of NRF2 alone, without disabling autophagy or causing injury, was sufficient to cause inflammasome-dependent HMGB1 release. In conclusion, HMGB1 release is a critical mechanism in hepatic pathogenesis under autophagy-deficient conditions and leads to HPC expansion as well as tumor progression.

Sterol regulatory element-binding proteins (SREBPs) are transcription factors that control lipid homeostasis. SREBP activation is regulated by a negative feedback loop in which sterols bind to SREBP cleavage-activating protein (SCAP), an escort protein essential for SREBP activation, or to insulin-induced genes (Insigs) (endoplasmic reticulum [ER] anchor proteins), sequestering the SREBP-SCAP-Insig complex in the ER. We screened a chemical library of endogenous molecules and identified 25-hydroxyvitamin D (25OHD) as an inhibitor of SREBP activation. Unlike sterols and other SREBP inhibitors, 25OHD impairs SREBP activation by inducing proteolytic processing and ubiquitin-mediated degradation of SCAP, thereby decreasing SREBP levels independently of the vitamin D receptor. Vitamin D supplementation has been proposed to reduce the risk of metabolic diseases, but the mechanisms are unknown. The present results suggest a previously unrecognized molecular mechanism of vitamin D-mediated lipid control that might be useful in the treatment of metabolic diseases.

Autophagy is important for hepatic homeostasis, nutrient regeneration, and organelle quality control. We investigated the mechanisms by which liver injury occurred in the absence of autophagy function. We found that mice deficient in autophagy because of the lack of autophagy-related gene 7 or autophagy-related gene 5, key autophagyrelated genes, manifested intracellular cholestasis with increased levels of serum bile acids, a higher ratio of tauromuricholic acid/taurocholic acid in the bile, increased hepatic bile acid load, abnormal bile canaliculi, and altered expression of hepatic transporters. In determining the underlying mechanism, we found that autophagy sustained and promoted the basal and up-regulated expression of farnesoid X receptor (Fxr ) in the fed and starved conditions, respectively. Consequently, expression of Fxr and its downstream genes, particularly bile salt export pump, and the binding of FXR to the promoter regions of these genes, were suppressed in autophagy-deficient livers. In addition, codeletion of nuclear factor erythroid 2-related factor 2 (Nrf2 ) in autophagy deficiency status reversed the FXR suppression. Furthermore, the cholestatic injury of autophagy-deficient livers was reversed by enhancement of FXR activity or expression, or by Nrf2 deletion. Conclusion: Together with earlier reports that FXR can suppress autophagy, our findings indicate that autophagy and FXR form a regulatory loop and deficiency of autophagy causes abnormal FXR functionality, leading to the development of intracellular cholestasis and liver injury. (Hepatology 2019;69:2196-2213).