MMAB promotes negative feedback control of cholesterol homeostasis

Leigh Goedeke, Alberto Canfrán-Duque, Noemi Rotllan, Balkrishna Chaube, Bonne M. Thompson, Richard G. Lee, Gary W. Cline, Jeffrey G. McDonald, Gerald I. Shulman, Miguel A. Lasunción, Yajaira Suárez and Carlos Fernández-Hernando ()
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Leigh Goedeke: Yale School of Medicine
Alberto Canfrán-Duque: Yale School of Medicine
Noemi Rotllan: Yale School of Medicine
Balkrishna Chaube: Yale School of Medicine
Bonne M. Thompson: University of Texas Southwestern Medical Center
Richard G. Lee: Cardiovascular Group, Antisense Drug Discovery, Ionis Pharmaceuticals
Gary W. Cline: Yale School of Medicine
Jeffrey G. McDonald: University of Texas Southwestern Medical Center
Gerald I. Shulman: Yale School of Medicine
Miguel A. Lasunción: Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRyCIS) and CIBER de Fisiopatología de la Obesidad y Nutrición (CIBERobn)
Yajaira Suárez: Yale School of Medicine
Carlos Fernández-Hernando: Yale School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract Intricate regulatory networks govern the net balance of cholesterol biosynthesis, uptake and efflux; however, the mechanisms surrounding cholesterol homeostasis remain incompletely understood. Here, we develop an integrative genomic strategy to detect regulators of LDLR activity and identify 250 genes whose knockdown affects LDL-cholesterol uptake and whose expression is modulated by intracellular cholesterol levels in human hepatic cells. From these hits, we focus on MMAB, an enzyme which catalyzes the conversion of vitamin B12 to adenosylcobalamin, and whose expression has previously been linked with altered levels of circulating cholesterol in humans. We demonstrate that hepatic levels of MMAB are modulated by dietary and cellular cholesterol levels through SREBP2, the master transcriptional regulator of cholesterol homeostasis. Knockdown of MMAB decreases intracellular cholesterol levels and augments SREBP2-mediated gene expression and LDL-cholesterol uptake in human and mouse hepatic cell lines. Reductions in total sterol content were attributed to increased intracellular levels of propionic and methylmalonic acid and subsequent inhibition of HMGCR activity and cholesterol biosynthesis. Moreover, mice treated with antisense inhibitors of MMAB display a significant reduction in hepatic HMGCR activity, hepatic sterol content and increased expression of SREBP2-mediated genes. Collectively, these findings reveal an unexpected role for the adenosylcobalamin pathway in regulating LDLR expression and identify MMAB as an additional control point by which cholesterol biosynthesis is regulated by its end product.

Date: 2021
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DOI: 10.1038/s41467-021-26787-7

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