↓ Figure 1. Semaglutide rebalances one-carbon
metabolism (OCM) along the progression of MASLD. (a) Metabolic alterations occur in the methionine
cycle, folate cycle, cysteine oxidation, choline oxidation, transsulfuration, glutathione synthesis, and
choline oxidation pathways in human MASLD. This was observed in 100 biopsy-proven MASLD patients versus
50 healthy controls. (b) Similar metabolite and transcriptional changes occur in the mouse DIO-MASH
model as in human MASLD. (d) In the mouse DIO-MASH model, semaglutide intervention for 12 weeks led to
the normalization or “over-correction” of key metabolites. (d) MASLD and ongoing fibrosis
are further associated with increased reactive oxygen species (ROS) production and increased expression
of the sequestosome protein p62 in fat-laden, ballooned hepatocytes, which drive the collapse of OCM
flux. AHCY: adenosylhomocysteinase; ALDH7A1: aldehyde dehydrogenase 7 family member A1; ALP: alkaline
phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BHMT2: betaine-homocysteine
S-methyltransferase 2; BMI: body mass index; CBS: cystathionine beta synthase; CDO1: cysteine
dioxygenase; CRP: C-reactive protein; CSAD: cysteine sulfinic acid decarboxylase; CTH: Cystathionine
γ-lyase; DIO: diet-induced obesity; DMGDH: dimethylglycine dehydrogenase; GCLC: glutamate-cysteine
ligase C; GCLM: glutamate-cysteine ligase M; GNMT: glycine N-methyltransferase; GPX2: glutathione
peroxidase 2; GPX4: glutathione peroxidase 4; GSS: glutathione synthetase; GSR: glutathione-disulfide
reductase; Hb1Ac: glycated hemoglobin; HDL: high-density lipoprotein; LDL: low-density lipoprotein;
MAT1A/2A/2B: methionine adenosyltransferase 1A/2A/2B; MTHFR: methylenetetrahydrofolate reductase; MTR:
methionine synthase; PIPOX: pipecolic acid and sarcosine oxidase; SARDH: sarcosine dehydrogenase;
SHMT1/2: serine hydroxymethyltransferase 1/2; VLDL: very-low-density lipoprotein.
