GPD1

GPD1 Full Name

glycerol-3-phosphate dehydrogenase 1 (soluble)

GPD1 Introduction

GPD1 encodes cytosolic NAD-dependent glycerol-3-phosphate dehydrogenase 1, a 349-amino-acid enzyme located on chromosome 12q12-q13 that sits at the crossroads of carbohydrate and lipid metabolism. It catalyzes the reversible redox reaction converting dihydroxyacetone phosphate (DHAP) and NADH into glycerol-3-phosphate (G3P) and NAD+. G3P serves as the obligate glycerol backbone for triglyceride and phospholipid biosynthesis, while the coupled mitochondrial isoform GPD2 completes the glycerol phosphate shuttle, transferring reducing equivalents from the cytosol into mitochondria and thereby linking glycolysis to oxidative phosphorylation. The enzyme is widely expressed in liver, adipose tissue, kidney, brain, and muscle, reflecting its broad metabolic responsibility.

Figure 1. Enzymatic reactions mediated by GPD1 and GPD2. (Source: Oh S, et al. 2024)

Mechanistically, GPD1 channels carbons from glucose-derived DHAP toward esterification with fatty acyl-CoA, governing hepatic triglyceride accumulation and adipocyte lipid storage. Ethanol exposure upregulates GPD1 and related glycolytic genes, augmenting incorporation of glucose into the glycerol moiety of triglycerides and contributing to alcoholic fatty liver. Loss of GPD1 disrupts the glycerol phosphate shuttle, alters the cytosolic NADH/NAD+ ratio, and impairs re-oxidation of reducing equivalents. This disturbance secondarily suppresses β-oxidation through reduced CPT1 and CPT2 activity, favors hepatic steatosis, and disrupts the metabolic flexibility needed for normal fasting-to-fed transitions in infants. Tissue-specific expression patterns explain why liver and adipose depots are most affected by GPD1 dysfunction.

Biallelic loss-of-function mutations in GPD1 were first identified in 2012 as the cause of transient infantile hypertriglyceridemia (TIH), a rare autosomal recessive disorder presenting in infancy with massive hepatomegaly, marked hypertriglyceridemia, fatty liver, and hepatic fibrosis. Subsequent reports have expanded the phenotype to include steatohepatitis, hepatic adenoma, hypoglycemia with insulin resistance, and adult-onset recurrent hypertriglyceridemic pancreatitis, with around 36 cases described worldwide to date. Management is largely supportive, with fenofibrate used in select patients to control progressive hypertriglyceridemia. Long-term outcomes are generally favorable, with hepatomegaly resolving in roughly one-third of patients and triglycerides normalizing in about one-third during follow-up, although liver fibrosis may persist.

Alternate Names for GPD1

GPD1; glycerol-3-phosphate dehydrogenase 1 (soluble); GPD-C; HTGTI; GPDH-C; glycerol-3-phosphate dehydrogenase [NAD(+)], cytoplasmic; glycerophosphate dehydrogenase; glycerol-3-phosphate dehydrogenase [NAD+], cytoplasmic;

• 1. Oh S, et al. Glycerol 3-phosphate dehydrogenases (1 and 2) in cancer and other diseases. Exp Mol Med. 2024 May;56(5):1066-1079.
  2. Basel-Vanagaite L, et al. Transient infantile hypertriglyceridemia, fatty liver, and hepatic fibrosis caused by mutated GPD1, encoding glycerol-3-phosphate dehydrogenase 1. Am J Hum Genet. 2012 Jan 13;90(1):49-60.