Disturbed intracellular folate homeostasis impairs autophagic flux and increases hepatocytic lipid accumulation.

Publisher: BioMed Central Country of Publication: England NLM ID: 101190720 Publication Model: Electronic Cited Medium: Internet ISSN: 1741-7007 (Electronic) Linking ISSN: 17417007 NLM ISO Abbreviation: BMC Biol Subsets: MEDLINE

Original Publication: [London] : BioMed Central, c2003-

Autophagy*/physiology ; Folic Acid*/metabolism ; Lipid Metabolism* ; Hepatocytes*/metabolism ; Homeostasis* ; Zebrafish*; Humans ; Animals ; Folic Acid Deficiency/metabolism

Background: Metabolic associated fatty liver disease (MAFLD), a prevalent liver disorder affecting one-third of the global population, encompasses a spectrum ranging from fatty liver to severe hepatic steatosis. Both genetic and lifestyle factors, particularly diet and nutrition, contribute to its etiology. Folate deficiency, a frequently encountered type of malnutrition, has been associated with the pathogenesis of MAFLD and shown to impact lipid deposition. However, the underlying mechanisms of this relationship remain incompletely understood. We investigated the impact of disturbed folate-mediated one-carbon metabolism (OCM) on hepatic lipid metabolism both in vitro using human hepatoma cells and in vivo using transgenic fluorescent zebrafish displaying extent-, stage-, and duration-controllable folate deficiency upon induction.
Results: Disturbed folate-mediated one-carbon metabolism, either by inducing folate deficiency or adding anti-folate drug, compromises autophagy and causes lipid accumulation in liver cells. Disturbed folate status down-regulates cathepsin L, a key enzyme involved in autophagy, through inhibiting mTOR signaling. Interfered mitochondrial biology, including mitochondria relocation and increased fusion-fission dynamics, also occurs in folate-deficient hepatocytes. Folate supplementation effectively mitigated the impaired autophagy and lipid accumulation caused by the inhibition of cathepsin L activity, even when the inhibition was not directly related to folate deficiency.
Conclusions: Disruption of folate-mediated OCM diminishes cathepsin L expression and impedes autophagy via mTOR signaling, leading to lipid accumulation within hepatocytes. These findings underscore the crucial role of folate in modulating autophagic processes and regulating lipid metabolism in the liver.
(© 2024. The Author(s).)

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MOST 109-2320-B-006-051 Ministry of Science and Technology, Taiwan; MOST 111-2311-B-006-0007 Ministry of Science and Technology, Taiwan; MOST D112-H8010 Ministry of Science and Technology, Taiwan; NSTC 112-2320-B-037-009 National Science and Technology Council

Keywords: Autophagy; Cathepsin L; Folate deficiency; Lipid metabolism

935E97BOY8 (Folic Acid)

Date Created: 20240703 Date Completed: 20240703 Latest Revision: 20240705

20240705

PMC11220954

10.1186/s12915-024-01946-6

38956599