Genetic interaction of DGAT2 and FAAH in the development of human obesity

Abstract

We detected two rare variants in DGAT2 with no significant difference between obese and lean individuals. One novel heterozygous nonsense variant c.382C > T (p.R128*) was identified in one obese subject but not in 219 lean subjects and another 1190 lean subjects. Notably, in vitro study showed that R128* mutation severely damaged the TG-biosynthesis ability of DGAT2, and all other R128* carriers in the pedigree were lean. Thus, we further identified a loss-of-function variant c. 944G > T (p.R315I) in FAAH in the proband inheriting from his obese father. Importantly, FAAH overexpression inhibited DGAT2 expression and TG synthesis, while R315I mutant largely eliminated this inhibitory effect. We first report loss-of-function mutations in DGAT2 and FAAH in one obese subject, which may interact with each other to affect the adiposity penetrance, providing a model of genetic interaction associated with human obesity.

Hepatocyte Deletion of Triglyceride‐Synthesis Enzyme Acyl CoA: Diacylglycerol Acyltransferase 2 Reduces Steatosis Without Increasing Inflammation or Fibrosis in Mice

“…Similar decreases were found in mice treated with AAV‐shDGAT2 or a DGAT2 inhibitor . A low HDL‐C level (~25 mg/dL) was also reported in a proband with nonsense mutation in DGAT2 , and an exome‐wide association study showed that humans who are heterozygous for a nonsense mutation in DGAT2 have lower HDL‐C levels . Our data show that a low HDL‐C phenotype is reproduced in a murine model where DGAT2 is deficient only in hepatocytes.…”

Identification of the Genetic Basis for the Large-tailed Phenotypic Trait in Han Sheep Through Integrated mRNA and miRNA Analysis of Tail Fat Tissue Samples

“…In mice, ACSL5 (Acyl-CoA synthetases 5) regulated systemic energy metabolism such that the knockout of this gene can prevent the onset of obesity and insulin resistance [50]. DGAT2 (Diacylgycerol acyltransferase 2) is an essential catalyst of triglyceride biosynthesis, which is important given that excessive triglyceride accumulation within adipose tissues is a key facet of obesity [51]. Overexpression of FAAH (Fatty acid amide hydrolase) can suppress DGAT2 expression and triglyceride synthesis, and these genes may interact with one another to in uence adiposity [51].…”

“…DGAT2 (Diacylgycerol acyltransferase 2) is an essential catalyst of triglyceride biosynthesis, which is important given that excessive triglyceride accumulation within adipose tissues is a key facet of obesity [51]. Overexpression of FAAH (Fatty acid amide hydrolase) can suppress DGAT2 expression and triglyceride synthesis, and these genes may interact with one another to in uence adiposity [51]. ACSS2 (Acetyl-CoA synthetase short-chain family member 2) codes for a cytosolic enzyme that catalyzes acetate activation for use in the context of lipid synthesis and energy production.…”

Association of VLDLR haplotypes with abdominal fat trait in ducks

“…Polymorphism-trait association studies cannot determine whether VLDLR is responsible for variation in a trait or whether a closely linked locus influences the trait. Many studies have revealed that obesity candidate genes were associated with genetics, nutritional disease, gastrointestinal and developmental disorders, and cancer (Castro et al, 2017;Ning et al, 2017). Peroxisome proliferator-activated receptor alpha (PPARα) and retinoid X receptor alpha (RXRα) were identified as central nodes, also called hub molecules (Kunej et al, 2013).…”