3-Hydroxyacyl CoA Dehydratase 2 Is Essential for Embryonic Development and Hepatic Metabolic Function Under a...

Area of Science:

• Biochemistry
• Metabolic pathways
• Molecular biology

Background:

• Carbohydrate conversion to fatty acids is crucial for energy storage and organ function.
• Previous research indicated Hacd2 deficiency alleviates high-fat diet-induced fatty liver and diabetes.
• The role of Hacd2 in organ development and metabolic homeostasis under low-fat, high-carbohydrate diets (LFHCD) requires further investigation.

Purpose of the Study:

• To explore the roles of Hacd2 in organ development and metabolic homeostasis under an LFHCD.
• To investigate the consequences of Hacd2 deficiency on embryonic development and metabolic parameters.

Main Methods:

• Germline deletion of Hacd2 to create Hacd2 knockout mice.
• Analysis of embryonic development using photography and hematoxylin-eosin staining.
• Assessment of metabolic parameters (body weight, adipose tissue, serum lipids, glucose metabolism) in Hacd2 knockout mice fed chow or LFHCD.
• RNA interference analysis to study Hacd2 inhibition during adipocyte differentiation.

Main Results:

• Germline deletion of Hacd2 impaired long-chain fatty acid synthesis, leading to embryonic abnormalities and lethality after 7.5 days.
• Hacd2 knockout mice on a chow diet showed normal development but had reduced inguinal white adipose tissue and altered glucose metabolism.
• Under LFHCD, Hacd2 deletion controlled body weight and white adipose tissue, reducing serum cholesterol and triglycerides.
• Unexpectedly, Hacd2 deletion under LFHCD resulted in liver enlargement, hepatocyte abnormalities, and inflammatory cell infiltration.
• Hacd2 inhibition reduced triglyceride levels and lipogenic gene expression during adipocyte differentiation.

Conclusions:

• Hacd2 is critical for embryonic development, with its deficiency causing embryonic lethality due to impaired fatty acid synthesis.
• Hacd2 plays a dual role in metabolic homeostasis; it is protective against diet-induced obesity and associated lipid abnormalities but essential for maintaining liver health under LFHCD.
• Targeted interventions for metabolic diseases involving Hacd2 must consider dietary context and potential adverse effects on liver function.