Variation in Acetyl-CoA Carboxylase Beta Gene and Its Effect on Carcass and Meat Traits in Gannan Yaks.

Acetyl-CoA carboxylase beta (ACACB) is a functional candidate gene that impacts fat deposition. In the present study, we sequenced exon 37-intron 37, exon 46-intron 46, and intron 47 of yak ACACB using hybrid pool sequencing to search for variants and genotyped the gene in 593 Gannan yaks via Kompetitive allele-specific polymerase chain (KASP) reaction to determine the effect of ACACB variants on carcass and meat quality traits. Seven single nucleotide polymorphisms were detected in three regions. Eight effective haplotypes and ten diplotypes were constructed. Among them, a missense variation g.50421 A > G was identified in exon 37 of ACACB, resulting in an amino acid shift from serine to glycine. Correlation analysis revealed that this variation was associated with the cooking loss rate and yak carcass weight (p = 0.024 and 0.012, respectively). The presence of haplotypes H5 and H6 decreased Warner-Bratzler shear force (p = 0.049 and 0.006, respectively), whereas that of haplotypes H3 and H4 increased cooking loss rate and eye muscle area (p = 0.004 and 0.034, respectively). Moreover, the presence of haplotype H8 decreased the drip loss rate (p = 0.019). The presence of one and two copies of haplotypes H1 and H8 decreased the drip loss rate (p = 0.028 and 0.004, respectively). However, haplotype H1 did not decrease hot carcass weight (p = 0.011), whereas H3 increased the cooking loss rate (p = 0.007). The presence of one and two copies of haplotype H6 decreased Warner-Bratzler shear force (p = 0.014). The findings of the present study suggest that genetic variations in ACACB can be a preferable biomarker for improving yak meat quality.

ACACB is a novel metabolism-related biomarker in the prediction of response to cetuximab therapy inmetastatic colorectal cancer.

Cetuximab is one of the most valuable targeted therapy monoclonal antibodies in the treatment of metastatic colorectal cancer (CRC). However, the mechanisms affecting cetuximab resistance in CRC treatment remain unclear. Metabolism, especially fatty acid metabolism, has been reported to play an important role in tumor treatment. The correlation between cetuximab resistance and metabolism and whether it can be a new biomarker to evaluate the sensitivity of cetuximab in CRC treatment still need to be further explored. In this study, we perform a comprehensive analysis to confirm the relationship between fatty acid metabolism and cetuximab resistance, and the differentially expressed genes (DEGs) related to cetuximab drug resistance in CRC are screened by bioinformatics technology. We find that acetyl-CoA carboxylase beta (ACACB), ADH1C, CES1, MGLL, FMO5, and GPT are the hub DEGs, and ACACB is the most important biomarker among them. In addition, we systematically analyze the role of ACACB in the tumorigenesis of CRC, including tissue expression, CRC cell growth, cetuximab sensitivity, and potential downstream pathways, by using bioinformatics techniques, in vitro experiments and clinical cohort validation. Our results confirm that cetuximab resistance is correlated with metabolism. ACACB can lead to decreased sensitivity to cetuximab in CRC, and its mechanism may be related to EGFR phosphorylation, which could affect the activation of the mTOR/Akt signaling pathway and regulation of CDT1-, cyclin D1-, and p21-related cell cycle modulation.

The ACACB gene rs2268388 polymorphism is associated with nephropathy in Caucasian patients with diabetes: a meta-analysis.

To date, case-control studies on the association between a single-nucleotide polymorphism (SNP), rs2268388, in the acetyl-coenzyme A carboxylase beta (ACACB) gene and diabetic nephropathy have provided controversial results. To clarify the effect of rs2268388 on the risk of diabetic nephropathy, a meta-analysis of all case-control studies was performed. The fixed effects and random effects models showed that the C allele was associated with a decreased susceptibility risk of diabetic nephropathy compared with the T allele among Caucasian patients with diabetes. The contrast of the recessive model produced the same pattern of results as the allele contrast. Our pooled data suggest a significant association exists between rs2268388 and diabetic nephropathy among Caucasian patients with diabetes.

Combination of lipid metabolism alterations and their sensitivity to inflammatory cytokines in human lipin-1-deficient myoblasts.

Lipin-1 deficiency is associated with massive rhabdomyolysis episodes in humans, precipitated by febrile illnesses. Despite well-known roles of lipin-1 in lipid biosynthesis and transcriptional regulation, the pathogenic mechanisms leading to rhabdomyolysis remain unknown. Here we show that primary myoblasts from lipin-1-deficient patients exhibit a dramatic decrease in LPIN1 expression and phosphatidic acid phosphatase 1 activity, and a significant accumulation of lipid droplets (LD). The expression levels of LPIN1-target genes [peroxisome proliferator-activated receptors delta and alpha (PPARδ, PPARα), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), acyl-coenzyme A dehydrogenase, very long (ACADVL), carnitine palmitoyltransferase IB and 2 (CPT1B and CPT2)] were not affected while lipin-2 protein level, a closely related member of the family, was increased. Microarray analysis of patients' myotubes identified 19 down-regulated and 51 up-regulated genes, indicating pleiotropic effects of lipin-1 deficiency. Special attention was paid to the up-regulated ACACB (acetyl-CoA carboxylase beta), a key enzyme in the fatty acid synthesis/oxidation balance. We demonstrated that overexpression of ACACB was associated with free fatty acid accumulation in patients' myoblasts whereas malonyl-carnitine (as a measure of malonyl-CoA) and CPT1 activity were in the normal range in basal conditions accordingly to the normal daily activity reported by the patients. Remarkably ACACB invalidation in patients' myoblasts decreased LD number and size while LPIN1 invalidation in controls induced LD accumulation. Further, pro-inflammatory treatments tumor necrosis factor alpha+Interleukin-1beta(TNF1α+IL-1ß) designed to mimic febrile illness, resulted in increased malonyl-carnitine levels, reduced CPT1 activity and enhanced LD accumulation, a phenomenon reversed by dexamethasone and TNFα or IL-1ß inhibitors. Our data suggest that the pathogenic mechanism of rhabdomyolysis in lipin-1-deficient patients combines the predisposing constitutive impairment of lipid metabolism and its exacerbation by pro-inflammatory cytokines.

Mechanism of the development of nonalcoholic steatohepatitis after pancreaticoduodenectomy.

BACKGROUND AND AIM: It is recognized that nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), may develop after pancreaticoduodenectomy (PD). However, the mechanism of NASH development remains unclear. This study aimed to examine the changes in gene expression associated with NASH occurrence following PD. METHODS: The expression of genes related to fatty acid/triglyceride (FA/TG) metabolism and inflammatory signaling was examined using liver samples obtained from 7 post-PD NASH patients and compared with 6 healthy individuals and 32 conventional NASH patients. RESULTS: The livers of post-PD NASH patients demonstrated significant up-regulation of the genes encoding CD36, FA-binding proteins 1 and 4, acetyl-coenzyme A carboxylase α, diacylglycerol acyltransferase 2, and peroxisome proliferator-activated receptor (PPAR) γ compared with normal and conventional NASH livers. Although serum apolipoprotein B (ApoB) and TG were decreased in post-PD NASH patients, the mRNAs of ApoB and microsomal TG transfer protein were robustly increased, indicating impaired TG export from the liver as very-low-density lipoprotein (VLDL). Additionally, elevated mRNA levels of myeloid differentiation primary response 88 and superoxide dismutases in post-PD NASH livers suggested significant activation of innate immune response and augmentation of oxidative stress generation. CONCLUSIONS: Enhanced FA uptake into hepatocytes and lipogenesis, up-regulation of PPARγ, and disruption of VLDL excretion into the circulation are possible mechanisms of steatogenesis after PD. GENERAL SIGNIFICANCE: These results provide a basis for understanding the pathogenesis of NAFLD/NASH following PD.