Defects in long‐chain 3‐hydroxy acyl‐CoA dehydrogenase lead to hepatocellular carcinoma: A novel etiology of hepatocellular carcinoma

Abstract

The incidence of both nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) have been increasing at an alarming rate. Little is known about NAFLD without cirrhosis as a risk for HCC. Here we report, for the first time, generation of a mouse model with a defect in long-chain 3-hydoxy acyl-CoA dehydrogenase (LCHAD). The LCHAD exon 15 deletion was embryonic lethal to the homozygous mice whereas heterozygous mice (HT) develop significant hepatic steatosis starting at young age (3 months old) and HCC at older age (>13 months old) without any evidence of fibrosis or cirrhosis. None of the wild-type (WT) mice developed steatosis and HCC (n = 39), whereas HT-LCHAD mice (n = 41) showed steatosis and~20% (8/41) developed liver masses with histological features of HCC. Proteomic analysis of liver tissues from WT-mice and HT-mice with no signs of HCC was conducted. Proteins with significant changes in abundance were identified by mass spectrometry. Abundance of 24 proteins was significantly different (p < 0.01) between WT and HT-LCHAD mice. The proteins found to vary in abundance are associated with different cellular response processes ranging from intermediary metabolism of carbohydrate, protein and lipid to oxidative stress, signal transduction and the process of tumorigenesis. Protein expression pattern of the HT-LCHAD mouse liver indicates predisposition to HCC and suggests that impaired hepatic mitochondrial fatty acid oxidation plays an important role in the development and progression of HCC. To assess the implication of these studies in human disease, we demonstrated significant downregulation of HADHA transcripts in HCC patients.

HADHA alleviates hepatic steatosis and oxidative stress in NAFLD via inactivation of the MKK3/MAPK pathway

“…HADHA, a fatty acid β-oxidation-related factor, mediates lipid programming to regulate multiple cellular programs, such as apoptosis, fat metabolism and mitochondrial function 26 , 44 , 45 , 46 , 47 . Increasing research has shown the important role of HADHA in metabolic dysfunction in the liver.…”

Abnormal expression of HADH, an enzyme of fatty acid oxidation, affects tumor development and prognosis (Review)

“…in a model of oral cancer, HadHB is expressed at low levels (21); HadHa is a TSG in esophageal cancer (26) and Bc (58) and HadHB is a TSG in crc (44). HadHa is one of the liver cancer models and HadHa is expressed at low levels (29). in 11 organs, the HadH is involved in fatty acid oxidation and located in 2p23 (70).…”

“…These results suggest that HadHa is associated with tumor differentiation and altered fatty acid β-oxidation. To verify that fatty acid β-oxidation disorder is associated with the development of hepatocellular carcinoma (Hcc) without cirrhosis, Khare et al (29) established a new mouse model. The study revealed that a mouse model deficient in long-chain 3-hydroxyacyl-coa dehydrogenase (lcHad) developed Hcc at an early age and demonstrated altered expression of early cancer markers.…”

Modeling Rare Human Disorders in Mice: The Finnish Disease Heritage

“…Early studies suggested that defects in mitochondrial energy metabolism might underlay the skeletal muscle defects, and this has been supported by in vitro studies with mitochondria isolated from rat skeletal muscle [173][174][175]. Homozygote Hadha KO mice with exon 15 deletion are reported to result in either early postnatal or embryonic lethality, while heterozygosity leads to hepatic steatosis at a young age (3 months) and hepatocellular carcinoma without cirrhosis at an older age (>13 months) [70,176].…”