So Young Bu

Adipose triglyceride lipase is a major hepatic lipase that regulates triacylglycerol turnover and fatty acid signaling and partitioning

Despite advances in our understanding of the ways in which nutrient oversupply and triacylglycerol (TAG) anabolism contribute to hepatic steatosis, little is known about the lipases responsible for regulating hepatic TAG turnover. Recent studies have identified adipose triglyceride lipase (ATGL) as a major lipase in adipose tissue, although its role in the liver is largely unknown. Thus, we tested the contribution of ATGL to hepatic lipid metabolism and signaling. Adenovirus‐mediated knockdown of hepatic ATGL resulted in steatosis in mice and decreased hydrolysis of TAG in primary hepatocyte cultures and in vitro assays. In addition to altering TAG hydrolysis, ATGL was shown to play a significant role in partitioning hydrolyzed fatty acids between metabolic pathways. Although ATGL gain and loss of function did not alter hepatic TAG secretion, fatty acid oxidation was increased by ATGL overexpression and decreased by ATGL knockdown. The effects on fatty acid oxidation coincided with decreased expression of peroxisome proliferator‐activated receptor α (PPAR‐α) and its target genes in mice with suppressed hepatic ATGL expression. However, PPAR‐α agonism was unable to normalize the effects of ATGL knockdown on PPAR‐α target gene expression, and this suggests that ATGL influences PPAR‐α activity independently of ligand‐induced activation. Conclusion: Taken together, these data show that ATGL is a major hepatic TAG lipase that plays an integral role in fatty acid partitioning and signaling to control energy metabolism. (HEPATOLOGY 2011)

Suppression of Long Chain Acyl-CoA Synthetase 3 Decreases Hepatic de Novo Fatty Acid Synthesis through Decreased Transcriptional Activity

Long chain acyl-CoA synthetases (ACSL) and fatty acid transport proteins (FATP) activate fatty acids to acyl-CoAs in the initial step of fatty acid metabolism. Numerous isoforms of ACSL and FATP exist with different tissue distribution patterns, intracellular locations, and substrate preferences, suggesting that each isoform has distinct functions in channeling fatty acids into different metabolic pathways. Because fatty acids, acyl-CoAs, and downstream lipid metabolites regulate various transcription factors that control hepatic energy metabolism, we hypothesized that ACSL or FATP isoforms differentially regulate hepatic gene expression. Using small interference RNA (siRNA), we knocked down each liver-specific ACSL and FATP isoform in rat primary hepatocyte cultures and subsequently analyzed reporter gene activity of numerous transcription factors and performed quantitative mRNA analysis of their target genes. Compared with control cells, which were transfected with control siRNA, knockdown of acyl-CoA synthetase 3 (ACSL3) significantly decreased reporter gene activity of several lipogenic transcription factors such as peroxisome proliferator activation receptor-γ, carbohydrate-responsive element-binding protein, sterol regulatory element-binding protein-1c, and liver X receptor-α and the expression of their target genes. These findings were further supported by metabolic labeling studies that showed [1-14C]acetate incorporation into lipid extracts was decreased in cells treated with ACSL3 siRNAs and that ACSL3 expression is up-regulated in ob/ob mice and mice fed a high sucrose diet. ACSL3 knockdown decreased total acyl-CoA synthetase activity without substantially altering the expression of other ACSL isoforms. In summary, these results identify a novel role for ACSL3 in mediating transcriptional control of hepatic lipogenesis.

Hepatic long-chain acyl-CoA synthetase 5 mediates fatty acid channeling between anabolic and catabolic pathways

Long-chain acyl-CoA synthetases (ACSLs) and fatty acid transport proteins (FATPs) activate fatty acids (FAs) to acyl-CoAs prior to their downstream metabolism. Of numerous ACSL and FATP isoforms, ACSL5 is expressed predominantly in tissues with high rates of triacylglycerol (TAG) synthesis, suggesting it may have an anabolic role in lipid metabolism. To characterize the role of ACSL5 in hepatic energy metabolism, we used small interference RNA (siRNA) to knock down ACSL5 in rat primary hepatocytes. Compared with cells transfected with control siRNA, suppression of ACSL5 expression significantly decreased FA-induced lipid droplet formation. These findings were further extended with metabolic labeling studies showing that ACSL5 knockdown resulted in decreased [1-14C]oleic acid or acetic acid incorporation into intracellular TAG, phospholipids, and cholesterol esters without altering FA uptake or lipogenic gene expression. ACSL5 knockdown also decreased hepatic TAG secretion proportionate to the observed decrease in neutral lipid synthesis. ACSL5 knockdown did not alter lipid turnover or mediate the effects of insulin on lipid metabolism. Hepatocytes treated with ACSL5 siRNA had increased rates of FA oxidation without changing PPAR-α activity and target gene expression. These results suggest that ACSL5 activates and channels FAs toward anabolic pathways and, therefore, is an important branch point in hepatic FA metabolism.

Lipocalin 2 is a selective modulator of peroxisome proliferator-activated receptor-γ activation and function in lipid homeostasis and energy expenditure

We have previously identified lipocalin 2 (Lcn2) as a cytokine playing a critical role in the regulation of body fat mass, lipid metabolism, and insulin resistance. Lcn2 deficiency reduces PPARγ gene expression in adipocytes. In this study, we investigated the role of Lcn2 in PPARγ activation and function via assessing the insulin sensitization and fatty acid (FA) homeostasis of PPARγ agonist in high‐fat diet (HFD)‐induced obesity in Lcn2−/− mice. We found that rosiglitazone (Rosi) significantly improved insulin sensitivity in Lcn2−/− mice as effectively as in wild‐type (WT) mice; unfed‐state levels of blood glucose, free FAs, and triglycerides (TGs) were significantly reduced after a 25‐d treatment of Rosi in Lcn2−/− mice. However, Rosi action on fat deposition and FA homeostasis was altered; Rosi‐induced body weight and subcutaneous fat gain and liver lipid accumulation were markedly lessened in Lcn2−/− mice. The results of in vivo metabolic labeling showed that Rosi markedly reduced de novo lipogenesis in adipose tissue of Lcn2−/− mice. In brown adipose tissue (BAT), the expression of the genes functioning in TG hydrolysis and mitochondrial oxidation was up‐regulated more in Lcn2−/− than in WT mice. Most strikingly, Rosi stimulated significantly higher levels of uncoupling protein‐1 expression in BAT, and completely rescued cold intolerance in Lcn2−/− mice. We demonstrate that Lcn2 is a critical selective modulator of PPARγ activation and function in lipid homeostasis and energy expenditure.—Jin, D., Guo, H., Bu, Y. S., Zhang, Y., Hannaford, J., Mashek, D. G., Chen, X. Lipocalin 2 is a selective modulator of peroxisome proliferator‐activated receptor‐γ activation and function in lipid homeostasis and energy expenditure. FASEB J. 25, 754–764 (2011). www.fasebj.org

Hepatic ATGL knockdown uncouples glucose intolerance from liver TAG accumulation

Adipose triglyceride lipase (ATGL) is the predominant triacylglycerol (TAG) hydrolase in mammals; however, the tissue‐specific effects of ATGL outside of adipose tissue have not been well characterized. Hence, we tested the contribution of hepatic ATGL on mediating glucose tolerance and insulin action. Glucose or insulin tolerance tests and insulin signaling were performed in C57BL/6 mice administered control (nongene specific shRNA) or Atgl shRNA adenoviruses. Glucose and lipid metabolism assays were conducted in primary hepatocytes isolated from mice transduced with control or Atgl shRNA adenoviruses. Knocking down hepatic ATGL completely abrogated the increase in serum insulin following either 1 or 12 wk of feeding a high‐fat (HF) diet despite higher hepatic TAG content. Glucose tolerance tests demonstrated that ATGL knockdown normalized glucose tolerance in HF‐diet‐fed mice. The observed improvements in glucose tolerance were present despite unaltered hepatic insulin signaling and increased liver TAG. Mice with suppressed hepatic ATGL had reduced hepatic glucose production in vivo, and hepatocytes isolated from Atgl shRNA‐treated mice displayed a 26% decrease in glucose production and a 38% increase in glucose oxidation compared to control cells. Taken together, these data suggest that hepatic ATGL knockdown enhances glucose tolerance by increasing hepatic glucose utilization and uncouples impairments in insulin action from hepatic TAG accumulation.—Ong, K. T., Mashek, M. T., Bu, SY., Mashek, D. G. Hepatic ATGL knockdown uncouples glucose intolerance from liver TAG accumulation. FASEB J. 27, 313–321 (2013). www.fasebj.org

Integrated Regulation of Hepatic Lipid and Glucose Metabolism by Adipose Triacylglycerol Lipase and FoxO Proteins

Metabolism is a highly integrated process that is coordinately regulated between tissues and within individual cells. FoxO proteins are major targets of insulin action and contribute to the regulation of gluconeogenesis, glycolysis, and lipogenesis in the liver. However, the mechanisms by which FoxO proteins exert these diverse effects in an integrated fashion remain poorly understood. We report that FoxO proteins also exert important effects on intrahepatic lipolysis and fatty acid oxidation via the regulation of adipose triacylglycerol lipase (ATGL), which mediates the first step in lipolysis, and its inhibitor, the G0/S1 switch 2 gene (G0S2). We also find that ATGL-dependent lipolysis plays a critical role in mediating diverse effects of FoxO proteins in the liver, including effects on gluconeogenic, glycolytic, and lipogenic gene expression and metabolism. These results indicate that intrahepatic lipolysis plays a critical role in mediating and integrating the regulation of glucose and lipid metabolism downstream of FoxO proteins.

Anticarcinogenic effect of quercetin by inhibition of insulin-like growth factor (IGF)-1 signaling in mouse skin cancer.

It has been shown that dysregulation of IGF-1 signaling is associated with tumor incidence and progression, whereas blockade of the signaling can effectively inhibit carcinogenesis. Although several mechanisms of anticancer activity of quercetin were proposed, molecular targets of quercetin have not been identified yet. Hence, we assessed the effect of quercetin on IGF-1 signaling inhibition in BK5.IGF-1 transgenic (Tg) mice, which over-expresses IGF-1 in the skin epidermis. A quercetin diet (0.02% wt/wt) for 20 weeks remarkably delayed the incidence of skin tumor by 2 weeks and reduced tumor multiplicity by 35% in a 7,12-dimethylbenz(a)anthracene (DMBA)-tetradecanoyl phorbol-13-acetate (TPA) two stage mouse skin carcinogenesis protocol. Moreover, skin hyperplasia in Tg mice was significantly inhibited by a quercetin supplementation. Further analysis of the MT1/2 skin papilloma cell line showed that a quercetin treatment dose dependently suppressed IGF-1 induced phosphorylation of the IGF-1 receptor (IGF-1R), insulin receptor substrate (IRS)-1, Akt and S6K; however, had no effect on the phosphorylation of PTEN. Additionally, the quercetin treatment inhibited IGF-1 stimulated cell proliferation in a dose dependent manner. Taken together, these data suggest that quercetin has a potent anticancer activity through the inhibition of IGF-1 signaling.

Study of Dietary Attitudes and Diet Management of Married Immigrant Women in Korea according to Residence Period

ABSTRACT The purpose of this study was to examine the dietary attitudes and meal management of married immigrant women according to residence period in Korea. The study was conducted by administering a questionnaire survey to 220 married immigrant women in Korea. More than one third of the immigrant women who stayed in Korea less than 3 years tended to eat a limited variety of foods. Irregularity of meal time decreased as residence time period increased (P＜0.05). As immigrant women stayed longer in Korea, they became more responsible for the diet of their family (P＜0.001) and had more time to share breakfast and dinner with all family members (P＜0.05). Nearly half of immigrant women in all residence periods indicated their husbands family as the most influential factor in acquiring Korean foods (P＜0.05). Immigrant women became more fa-miliar with Korean cooking and recognition of nutritious foods (P＜0.001) the longer they lived in Korea and more enjoyable meal times with family (P＜0.05). In summary, as the period of residence in Korea increased, the dietary attitudes of immigrant women became more positive towards Korean food and diet culture. Further, immigrant women became more responsible for guiding childrens dietary habits and offering healthy foods to their family as residence period increased. Therefore, the government and social programs should conduct constant and organized lessons on Korean culture and cooking according to residence period for im-migrant women to build up stable and positive dietary attitudes.

Daily calcium intake and its relation to blood pressure, blood lipids, and oxidative stress biomarkers in hypertensive and normotensive subjects

Several studies revealed that low calcium intake is related to high prevalence of cardiovascular diseases such as hypertension. The prevalence of hypertension is high in Koreans along with their low dietary calcium consumption. Thus, the aim of this study was to evaluate the status of calcium intake between the hypertension and normotension groups and to investigate the correlation between dietary calcium intake and blood pressure, blood lipid parameters, and blood/urine oxidative stress indices. A total of 166 adult subjects participated in this study and were assigned to one of two study groups: a hypertension group (n = 83) who had 140 mmHg or higher in systolic blood pressure (SBP) or 90 mmHg or higher in diastolic blood pressure (DBP), and an age- and sex-matched normotension group (n = 83, 120 mmHg or less SBP and 80 mmHg or less DBP). The hypertension group consumed 360.5 mg calcium per day, which was lower than that of the normotension group (429.9 mg) but not showing significant difference. In the hypertension group, DBP had a significant negative correlation with plant calcium (P < 0.01) after adjusting for age, gender, body mass index (BMI), and energy intake. In the normotension group, total calcium and animal calcium intake were significantly and positively correlated with serum triglycerides. No significant relationship was found between calcium intake and blood/urine oxidative stress indices in both groups. Overall, these data suggest reconsideration of food sources for calcium consumption in management of the blood pressure or blood lipid profiles in both hypertensive and normotensive subjects.

Dietary Intake Ratios of Calcium-to-Phosphorus and Sodium-to-Potassium Are Associated with Serum Lipid Levels in Healthy Korean Adults

The purpose of this study was to identify food sources for major minerals such as calcium (Ca), phosphorus (P), sodium (Na) and potassium (K), and to evaluate the relationship between dietary intake of these minerals and serum lipids in healthy Korean adults. A total of 132 healthy men and women completed a physical examination and dietary record and provided blood samples for lipid profile analysis. Results showed the following daily average mineral intakes: 373.4 mg of calcium, 806.0 mg of phosphorous, 3685.8 mg of sodium, and 1938.3 mg of potassium. The calcium-to-phosphorus and sodium-to-potassium ratio was about 0.5 and 2.0, respectively. The primary sources for each mineral were: vegetables (24.9%) and fishes (19.0%) for calcium, grains (31.4%) for phosphorus, seasonings (41.6%) and vegetables (27.0%) for sodium, and vegetables (30.6%) and grains (18.5%) for potassium. The correlation analysis, which has been adjusted for age, gender, total food consumption, and energy intake, showed significantly positive correlations between Ca/P and serum HDL cholesterol levels, between Na intake and the level of serum total cholesterol, and between Na/K and the level of serum cholesterol and LDL cholesterol. Our data indicates that the level of mineral consumption partially contributes to serum lipid profiles and that a diet consisting of a low Ca/P ratio and a high Na/K ratio may have negative impacts on lipid metabolism.