HADH

Official Full Name

hydroxyacyl-CoA dehydrogenase

Organism

Homo sapiens

GeneID

3033

Background

This gene is a member of the 3-hydroxyacyl-CoA dehydrogenase gene family. The encoded protein functions in the mitochondrial matrix to catalyze the oxidation of straight-chain 3-hydroxyacyl-CoAs as part of the beta-oxidation pathway. Its enzymatic activity is highest with medium-chain-length fatty acids. Mutations in this gene cause one form of familial hyperinsulinemic hypoglycemia. The human genome contains a related pseudogene of this gene on chromosome 15. [provided by RefSeq, May 2010]

Synonyms

HAD; HCDH; HHF4; HADH1; SCHAD; HADHSC; MSCHAD;

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Detailed Information

Recent Research Progress

HADH encodes the enzyme short chain 3-hydroxyacyl-CoA dehydro-genase, which is a key enzyme and catalyzes the third step in mitochondrial fatty acid oxidation. It catalyses the conversion of L3-hydroxacyl CoAs of variable chain length to their corresponding 3-ketoacyl CoAs. This enzyme exerts highest activity to 3-hydroxybutyryl-CoA. And it is active with substrates up to C16 though activity decreases with increasing chain length. And Vredendaal et al. mapped the HADH gene to Chr4q22-26.

The HADH gene is expressed in most tissues but enzyme activity is particularly high in the pancreas and the islets of Langerhans. In addition, studies have shown that basal and glucose-stimulated insulin secretion increases when HADH expression is inhibited. According to related research, HADH expression is regulated by transcription factors that are essential for pancreatic β-cells differentiation and function such as Foxa2. Moreover, mice which have Foxa2 knocked out specifically in the β-cells show a 3-fold downregulation of HADH mRNA and are severely hyperinsulinaemic and hypoglycaemic. In conclusion, these researches suggest an important role for HADH in regulation of insulin secretion.

Some researches proved that recessively inherited loss of function mutations in HADH cause protein-induced hyperinsulinemic hypoglycemia(HH). Filling et al. proposed the existence of an interaction between HADH and glutamate dehydrogenase(GDH) in the pancreatic β-cell. It could be hypothesized that mutations in HADH cause protein sensitive HH via the GDH axis. While HADH interacts with GDH, HADH acts as an inhibitor of GDH against the leucine stimulated insulin secretion. Another study has shown that loss of protein interaction between HADH and GDH causes an over activation of GDH. Future studies regarding the interaction of HADH with other proteins and the effects of amino acids are required to elucidate the mechanisms involved and uncover how HADH acts and interacts in pancreatic β-cells to mediate insulin secretion.

One study has shown that the expression of HADH is decreased during gastric cancer progression. Importantly, HADH downregulation was associated with increased expression of p-Akt and reduced expression of PTEN in the gastric carcinoma (GC) tumor samples. Related analysis revealed that knockdown of HADH promoted the proliferation, migration and invasion of the gastric cancer cells MKN45 via activation of Akt signaling pathway. By contrast, HADH overexpression inhibited the migration and invasion of MKN45 cells. This proves that HADH knockdown promotes tumor cell migration and invasion(gastric cancer progression) through activation of Akt signaling pathway. How does HADH influence Akt signaling? The downregulation of HADH could slow down β-oxidation, which leads to accumulation of fatty acids that inhibit the transcription of PTEN which is a major negative regulator of the PI3K/Akt signaling pathway. Therefore, PTEN repression will lead to Akt activation in cells with HADH knockdown.

References:

Shen C, et al. Downregulation of HADH promotes gastric cancer progression via Akt signaling pathway. Oncotarget, 2017, 8(44).
Satapathy A K, et al. Hyperinsulinemic hypoglycemia of infancy due to novel HADH mutation in two siblings. Indian Pediatrics, 2016, 53(10):912-913.
Çamtosun E, et al. A Deep Intronic HADH Splicing Mutation (c.636+471G>T) in a Congenital Hyperinsulinemic Hypoglycemia Case: Long Term Clinical Course. Journal of Clinical Research in Pediatric Endocrinology, 2015, 7(2):144-147.

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