Hepatocellular BChE as a therapeutic target to ameliorate hypercholesterolemia through PRMT5 selective degradation to restore LDL receptor transcription

Life Sci. 2022 Mar 15:293:120336. doi: 10.1016/j.lfs.2022.120336. Epub 2022 Jan 19.

Abstract

Aims: Individuals with nonalcoholic hepatosteatosis (NAFLD) have a worse atherogenic lipoprotein profile and are susceptible to cardiovascular diseases. The MEK-ERK signaling cascades are central regulators of the levels of LDL receptor (LDLR), a major determinant of circulating cholesterol. It is elusive how hepatic steatosis contributes to dyslipidemia, especially hypercholesterolemia.

Main methods: The effects of BChE on signaling pathways were determined by immunoblotting in a BChE knockout hepatocyte cell line. DiI-LDL probe was used to explore the effect of BChE expression on LDL internalization. Co-immunoprecipitation and LC-MS were used to explore the interacting proteins with BChE. Finally, a hepatocyte-restricted BChE silencing mouse model was established by AAV8-Tbg-shRNA, and the hypercholesterolemia was induced by 65% kcal% high-fat, high-sucrose diet feeding.

Main findings: Here we demonstrate that butyrylcholinesterase (BChE) governs the LDL receptor levels and LDL uptake capacity through the MEK-ERK signaling cascades to promote Ldlr transcription. BChE interacts and co-localizes with PRMT5, a protein methylation modifier controlling the ERK signaling. PRMT5 regulates LDLR-dependent LDL uptake and is a substrate of chaperone-mediated autophagy (CMA). BChE deficiency induces the PRTM5 degradation dependent on CMA activity, possibly through facilitating the HSC70 (Heat shock cognate 71 kDa) recognition of PRMT5. Remarkably, in vivo hepatocyte-restricted BChE silencing reduces plasma cholesterol levels substantially. In contrast, the BChE knockout mice are predisposed to hypercholesterolemia.

Significance: Taken together, these findings outline a regulatory role for the BChE-PRMT5-ERK-LDLR axis in hepatocyte cholesterol metabolism, and suggest that targeting liver BChE is an effective therapeutic strategy to treat hypercholesterolemia.

Keywords: Chaperone-mediated autophagy; HSC70; Hepatocellular butyrylcholinesterase; LDL receptor; NAFLD and hypercholesterolemia; PRMT5.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Butyrylcholinesterase / deficiency*
  • Butyrylcholinesterase / genetics
  • Carbon Tetrachloride / toxicity
  • Hep G2 Cells
  • Hepatocytes / metabolism*
  • Humans
  • Hypercholesterolemia / genetics
  • Hypercholesterolemia / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Non-alcoholic Fatty Liver Disease / chemically induced
  • Non-alcoholic Fatty Liver Disease / genetics
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Protein-Arginine N-Methyltransferases / genetics
  • Protein-Arginine N-Methyltransferases / metabolism*
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism*
  • Transcription, Genetic / physiology*

Substances

  • Receptors, LDL
  • Carbon Tetrachloride
  • Prmt5 protein, mouse
  • Protein-Arginine N-Methyltransferases
  • Butyrylcholinesterase