Acetyl-CoA mediated autoacetylation of fatty acid synthase in de novo lipogenesis

De novo lipogenesis (DNL) is a highly regulated metabolic process, which is known to be activated through transcriptional regulation of lipogenic genes, including fatty acid synthase (FASN). Unexpectedly, we find that the expression of FASN protein remains unchanged during Drosophila larval development when lipogenesis is hyperactive. Instead, acetylation modification of FASN is highly upregulated in fast-growing larvae. We further show that lysine K813 is highly acetylated in developing larvae, and its acetylation is required for upregulated FASN activity, body fat accumulation, and normal development. Intriguingly, K813 is rapidly autoacetylated by acetyl-CoA in a dosage-dependent manner, independent of known acetyltransferases. Furthermore, the autoacetylation of K813 is mediated by a conserved P-loop-like motif (N-xx-G-x-A). In summary, this work uncovers a novel role of acetyl-CoA-mediated autoacetylation of FASN in developmental lipogenesis and reveals a self-regulatory system that controls metabolic homeostasis by linking acetyl-CoA, lysine acetylation, and DNL.

Maternal Obesogenic Diet Regulates Offspring Bile Acid Homeostasis and Hepatic Lipid Metabolism via the Gut Microbiome in Mice

Mice exposed in gestation to maternal high fat/high sucrose (HF/HS) diet develop altered bile acid (BA) homeostasis. We hypothesized that these reflect an altered microbiome and asked if microbiota transplanted from HF/HS offspring change hepatic BA and lipid metabolism to determine the directionality of effect. Female mice were fed HF/HS or chow (CON) for 6 weeks and bred with lean males. 16S sequencing was performed to compare taxa in offspring. Cecal microbiome transplantation (CMT) was performed from HF/HS or CON offspring into antibiotic treated mice fed chow or high fructose. BA, lipid metabolic, and gene expression analyses performed in recipient mice. Gut microbiomes from HF/HS offspring segregated from CON offspring, with increased Firmicutes to Bacteriodetes ratios and Verrucomicrobial abundance. Following CMT, HF/HS recipient mice had larger BA pools, and increased intrahepatic muricholic acid and decreased deoxycholic acid species. HF/HS recipient mice exhibited downregulated hepatic Mrp2, increased hepatic Oatp1b2, and decreased ileal Asbt mRNA expression. HF/HS recipient mice exhibited decreased cecal butyrate and increased hepatic expression of Il6. HF/HS recipient mice had larger livers, and increased intrahepatic triglyceride versus CON recipient mice after fructose feeding, with increased hepatic mRNA expression of lipogenic genes including Srebf1, Fabp1, Mogat1, and Mogat2. CMT from HF/HS offspring increased BA pool and shifted the composition of the intrahepatic BA pool. CMT from HF/HS donor offspring increased fructose-induced liver triglyceride accumulation. These findings support a causal role for vertical transfer of an altered microbiome in hepatic BA and lipid metabolism in HF/HS offspring.

Identification of Pre-Diabetic Biomarkers in the Progression of Diabetes Mellitus

Type 2 diabetes mellitus (T2DM) is a major global health issue. The development of T2DM is gradual and preceded by the pre-diabetes mellitus (pre-DM) stage, which often remains undiagnosed. This study aimed to identify novel pre-DM biomarkers in a high-fat diet (HFD)-induced pre-DM mouse model. Male C57BL/6J mice were fed either a chow diet or HFD for 12 weeks. Serum and liver samples were isolated in a time-dependent manner. Semi-quantitative assessment of secretory cytokines was performed by cytokine array analysis, and 13 cytokines were selected for further analysis based on the changes in expression levels in the pre-DM and T2DM stages. HFD-fed mice gained body weight and exhibited high serum lipid, liver enzyme, glucose, and insulin levels during the progression of pre-DM to T2DM. The mRNA expression of inflammatory and lipogenic genes was elevated in HFD-fed mice The mRNA expression of Fc receptor, IgG, low affinity Iib, lectin, galactose binding, soluble 1, vascular cell adhesion molecule 1, insulin-like growth factor binding protein 5, and growth arrest specific 6 was elevated in the pre-DM, which was confirmed by measuring protein levels. Our study identified novel pre-DM biomarkers that may help to delay or prevent the progression of T2DM.

The Effect of Rearing Conditions on Carcass Traits, Meat Quality and the Compositions of Fatty Acid and Amino Acid of LTL in Heigai Pigs

The present study evaluates the influence of captivity and grazing rearing conditions on the carcass traits, meat quality and fatty acid profiles of Heigai pigs. Ten Heigai pigs with market weight were randomly selected from both the indoor feeding farm and outdoor grazing farm groups (FF and GF; five pigs per group) for measuring production performance. The results showed that the shear force of longissimus thoracis et lumborum (LTL) in the GF group tended to increase (p = 0.06), and triglyceride and cholesterol contents in LTL and psoas major muscle (PMM) of the GF group significantly increased and decreased, respectively (p < 0.05). The proportion of saturated fatty acids (SFA) was significantly increased (p < 0.05) in the GF group. Meanwhile, the ratios of unsaturated fatty acid (UFA), polyunsaturated fatty acid (PUFA), monounsaturated fatty acid (MUFA) and the content of flavor amino acid of the LTL in the GF group were significantly decreased (p < 0.05). The GF upregulated the expression of MyHC-IIb and lipogenic genes, such as GLUT4 and LPL (p < 0.05), in LTL and PMM, but downregulated the expression of MyHC-I, MyHC-IIa, PPARγ and leptin (p < 0.05). In conclusion, these results suggested that the different rearing conditions can alter the meat qualities by mediating the muscle fiber type and lipid metabolism of Heigai pigs.

GR-mediated transcriptional regulation of m6A metabolic genes contributes to diet-induced fatty liver in hens

Background Glucocorticoid receptor (GR) mediated corticosterone-induced fatty liver syndrome (FLS) in the chicken by transactivation of Fat mass and obesity associated gene (FTO), leading to demethylation of N6-methyladenosine (m6A) and post-transcriptional activation of lipogenic genes. Nutrition is considered the main cause of FLS in the modern poultry industry. Therefore, this study was aimed to investigate whether GR and m6A modification are involved in high-energy and low protein (HELP) diet-induced FLS in laying hens, and if true, what specific m6A sites of lipogenic genes are modified and how GR mediates m6A-dependent lipogenic gene activation in HELP diet-induced FLS in the chicken. Results Laying hens fed HELP diet exhibit excess (P < 0.05) lipid accumulation and lipogenic genes activation in the liver, which is associated with significantly increased (P < 0.05) GR expression that coincided with global m6A demethylation. Concurrently, the m6A demethylase FTO is upregulated (P < 0.05), whereas the m6A reader YTHDF2 is downregulated (P < 0.05) in the liver of FLS chickens. Further analysis identifies site-specific demethylation (P < 0.05) of m6A in the mRNA of lipogenic genes, including FASN, SREBP1 and SCD. Moreover, GR binding to the promoter of FTO gene is highly enriched (P < 0.05), while GR binding to the promoter of YTHDF2 gene is diminished (P < 0.05). Conclusions These results implicate a possible role of GR-mediated transcriptional regulation of m6A metabolic genes on m6A-depenent post-transcriptional activation of lipogenic genes and shed new light in the molecular mechanism of FLS etiology in the chicken.

SREBP-1c and lipogenesis in the liver: an update

Sterol Regulatory Element Binding Protein-1c is a transcription factor that controls the synthesis of lipids from glucose in the liver, a process which is of utmost importance for the storage of energy. Discovered in the early nineties by B. Spiegelman and by M. Brown and J. Goldstein, it has generated more than 5000 studies in order to elucidate its mechanism of activation and its role in physiology and pathology. Synthetized as a precursor found in the membranes of the endoplasmic reticulum, it has to be exported to the Golgi and cleaved by a mechanism called regulated intramembrane proteolysis. We reviewed in 2002 its main characteristics, its activation process and its role in the regulation of hepatic glycolytic and lipogenic genes. We particularly emphasized that Sterol Regulatory Element Binding Protein-1c is the mediator of insulin effects on these genes. In the present review, we would like to update these informations and focus on the response to insulin and to another actor in Sterol Regulatory Element Binding Protein-1c activation, the endoplasmic reticulum stress.

208 MicroRNA Expression in Longissimus Muscle Biopsies During Feedlot Finishing of Angus Steers

Intramuscular fat or marbling (IMF) is highly desired in beef products due to its ability to improve carcass value. Studies indicate that finishing cattle on high concentrate diets increase marbling deposition over time-on-feed (TOF). Angus-cross steers (n = 7; 433 + 17 kg) were individually fed a high concentrate diet for a period of 124 d. Steers were weighed and ultrasounded every 30 d on feed. Longissimus muscle biopsies were taken between the 11th and 13th rib on alternating sides at d 0, 90, and 124. RNA was extracted from the biopsy samples and subjected to microRNA (miRNA) sequencing and qPCR for mRNA expression of key lipogenic genes. Data were analyzed with time-on-feed in the model. ADG was increased between d30 and d90 (P &lt; 0.05). The feed conversion ratio was lowest during d0 to d60 and increased from d90 to d124 (P &lt; 0.05). Fat thickness increased (P &lt; 0.05) between 90 to 124 d. Ultrasound intramuscular fat percentage increased (P &lt; 0.05) between 60 and 90 d. miRNA sequencing results showed that mir-122 was differentially expressed from d0 to d90 (6.72 log fold change; P = 0.0048) and from d0 to 124 (3.83 log fold change; P = 0.026). Several miRNA were down regulated (&gt; 2 log fold change; P &lt; 0.05) during TOF, which included miR-2411, -449a, -1197, -323, and -485. Relative expression of key lipogenic genes, stearoyl Co-A desaturase (SCD-1) and fatty acid synthase, were up-regulated (P &lt; 0.05) between d90 and 124 d. These results show that miR-122 appears to be a novel miRNA associated with marbling deposition and lipid metabolism.

Endocrine Disrupting Chemicals, Hormone Receptors, and Acne Vulgaris: A Connecting Hypothesis

The relationship between endocrine disrupting chemicals (EDCs) and the pathogenesis of acne vulgaris has yet to be explored in the literature. Acne vulgaris is a chronic inflammatory skin disease of the pilosebaceous unit. The pathogenesis of acne involves several hormonal pathways, including androgens, insulin-like growth factor 1(IGF-1), estrogens, and corticosteroids. EDCs influence these pathways primarily through two mechanisms: altering endogenous hormone levels and interfering with hormone receptor function. This review article describes the mechanistic links between EDCs and the development of acne lesions. Highlighted is the contributory role of androgen receptor ligands, such as bisphenol A (BPA) and mono-2-ethylhexyl Phthalate (MEHP), via upregulation of lipogenic genes and resultant exacerbation of cholesterol synthesis. Additionally discussed is the protective role of phytoestrogen EDCs in counteracting androgen-induced sebocyte maturation through attenuation of PPARy transcriptional activity (i.e., resveratrol) and restoration of estrogen-regulated TGF-B expression in skin cells (i.e., genistein). Examination of the relationship between EDCs and acne vulgaris may inform adjunctive avenues of treatment such as limiting environmental exposures, and increasing low-glycemic, plant-rich foods in the diet. With a better understanding of the cumulative role that EDCs play in acne, clinicians can be better equipped to treat and ultimately improve the lives of their patients.

Disruption of Adipose Tissue Metabolism by Glucocorticoids Is Attenuated With LXRβ Antagonism

Excessive exposure to glucocorticoids (GCs), either from endogenous overproduction of cortisol, or exogenous pharmacological GC treatment, potentiates the development of diabetes and obesity in a fat depot-specific manner. Undesirable metabolic side effects resulting from the activation of the glucocorticoid receptor (GR) remain a key limitation to the long-term therapeutic use of GCs as immunosuppressants. GC treatment disrupts the thermogenic function of brown adipose tissue (BAT) and enhances futile cycling within white adipose tissue (WAT). Mice lacking the liver X receptors (LXRs) were previously shown to have smaller AT depots with enhanced BAT activity compared to wildtype (WT) mice. We previously demonstrated that LXRβ is required to mediate the side effects of GCs in the liver but not the beneficial anti-inflammatory effects of GCs. The discovery of this GC/LXRβ cross-talk led to the hypothesis that LXRβ antagonism may be therapeutically beneficial to prevent GC-induced dysfunction in AT. To test this idea, LXRα-/- mice were treated for 5 days with vehicle, 5 mg/kg dexamethasone (Dex, a synthetic GC agonist), and/or 40 mg/kg GSK2033 (GSK, non-selective LXR antagonist). As expected, Dex-treated mice showed significant accumulation of lipids in BAT and were unable to maintain their body temperature when exposed to cold, yet GSK was able to protect against these effects. Dex increased body fat mass and caused adipocyte enlargement in WAT which was not observed in mice co-treated with GSK. At the transcriptional level, GSK attenuated Dex-mediated downregulation of thermogenic genes in BAT, and upregulation of lipogenic genes in WAT. Similar beneficial changes were confirmed in WT mice. The protection afforded by GSK against Dex-induced fat accumulation was confirmed to be cell-autonomous from studies in adipose-specific LXRβ-/- mice (AdβKO). Dex-dependent increases in lipolysis in gonadal WAT and plasma free fatty acids (FFA) were also attenuated by GSK co-treatment. With GSK co-treatment, Dex-induced liver steatosis was diminished suggesting that LXRβ antagonism attenuated FFA shuttling to the liver. The lipolytic and lipotoxic effects of Dex in AT and liver were largely abrogated in AdβKO along with improved systemic insulin sensitivity. Overall, our data suggest that LXRβ antagonism prevents disruption of BAT and WAT (and indirectly liver) function caused by GC treatment in an in vivo model, highlighting the potential role of LXRβ antagonists in combating the negative effects of excessive GC exposure on the development of diabetes and obesity. The identification of this novel mechanism of interrupting GC adipose tissue action suggests therapeutic targeting of LXRβ with an antagonist could improve the health of patients currently taking GCs to control inflammation but suffer the detrimental side effects of drug treatment.