Hepatic MDM2 Causes Metabolic Associated Fatty Liver Disease by Blocking Triglyceride‐VLDL Secretion via ApoB Degradation

Abstract

Dysfunctional triglyceride-very low-density lipoprotein (TG-VLDL) metabolism is linked to metabolic-associated fatty liver disease (MAFLD); however, the underlying cause remains unclear. The study shows that hepatic E3 ubiquitin ligase murine double minute 2 (MDM2) controls MAFLD by blocking TG-VLDL secretion. A remarkable upregulation of MDM2 is observed in the livers of human and mouse models with different levels of severity of MAFLD. Hepatocyte-specific deletion of MDM2 protects against high-fat high-cholesterol diet-induced hepatic steatosis and inflammation, accompanied by a significant elevation in TG-VLDL secretion. As an E3 ubiquitin ligase, MDM2 targets apolipoprotein B (ApoB) for proteasomal degradation through direct protein-protein interaction, which leads to reduced TG-VLDL secretion in hepatocytes. Pharmacological blockage of the MDM2-ApoB interaction alleviates dietary-induced hepatic steatohepatitis and fibrosis by inducing hepatic ApoB expression and subsequent TG-VLDL secretion. The effect of MDM2 on VLDL metabolism is p53-independent. Collectively, these findings suggest that MDM2 acts as a negative regulator of hepatic ApoB levels and TG-VLDL secretion in MAFLD. Inhibition of the MDM2-ApoB interaction may represent a potential therapeutic approach for MAFLD treatment.

VLDL Biogenesis and Secretion: It Takes a Village

“…At the start of this review, we raised the key question whether it will be possible to prevent or treat ASCVD by reducing VLDL secretion without increasing hepatic lipids. This is possible as we noted for VIGILIN, 15 MDM2, 20 TGH, 26,27 MIA2, 109 and SURF4 (in the study by Shen et al 157 but not in the study by Wang et al 37 ). In addition, in mice, hepatic steatosis is absent when microRNA-30c reduces plasma lipids 158 or when differential inhibition of triglyceride and phospholipid transfer activities of MTP dissociate impaired VLDL secretion from hepatic steatosis.…”

“…This was recently shown after hepatic deletion of MDM2 (murine double minute 2), a protein that acts as an E3 ubiquitin ligase and targets apoB for proteasomal degradation. 20 MDM2 is well known for its function as a negative regulator of the p53 tumor suppressor protein, and this was the first study showing that MDM2 also targets apoB100 for proteolysis. Liver-specific deletion of Mdm2 in mice on chow did not alter hepatic triglyceride levels, but on a high-fat, high-cholesterol diet, hepatic triglycerides were reduced by 50%.…”

“…This process is facilitated by numerous proteins involved in ER-associated degradation** (ERAD). Newly identified factors in this process include LZP (liver-specific zona pellucida domain-containing protein 19 ) and MDM2 (murine double minute 2 20 ). MTP is essential for stabilization and initial lipidation of apoB to form nascent VLDL.…”

“…153,154 Also, genome-wide association studies have identified variants in the VMP1 gene that are associated with circulating levels of LDL. 155,156 In several cases, including VIGILIN , 15 MDM2 , 20 and GP73 , 36 it is clear that the encoding genes are upregulated in humans with NASH or steatosis compared with normal livers. In the majority of cases, however, the biology of the new factors discussed in this review has not been studied in humans.…”

“…This was recently shown after hepatic deletion of MDM2 (murine double minute 2), a protein that acts as an E3 ubiquitin ligase and targets apoB for proteasomal degradation. 20 MDM2 is well known for its function as a negative regulator of the p53 tumor suppressor protein, and this was the first study showing that MDM2 also targets apoB100 for proteolysis. Liver-specific deletion of Mdm2 in mice on chow did not alter hepatic triglyceride levels, but on a In the outer leaflet of the hepatocyte ER, DGAT (diacylglyceride acyltransferase) 1 and 2, ACAT (acyl-coenzyme A:cholesterol acyltransferase), and PEMT (phosphatidylethanolamine N-methyltransferase) synthesize the main lipid components of VLDL (very-low-density lipoprotein), for example, triglycerides, cholesteryl esters, and phospholipids, respectively.…”