Fatty acid synthase and liver triglyceride metabolism: Housekeeper or messenger?

Jensen-Urstad, Anne P.L.; Semenkovich, Clay F.

doi:10.1016/j.bbalip.2011.09.017

Cited by 322 publications

(228 citation statements)

References 83 publications

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“…ACC can catalyze acetyl-CoA carboxylation to generate malonylCoA. Subsequently, FAS facilitates de novo biosynthesis of long-chain saturated fatty acids from malonyl-CoA; the resultant fatty acids are essential for TG synthesis via esterification [28,32]. Irisin protected GSIS and repressed apoptosis in isolated mouse islets under glucolipotoxic conditions.…”

Section: Discussionmentioning

confidence: 99%

Irisin Ameliorates Glucolipotoxicity-Associated β-Cell Dysfunction and Apoptosis via AMPK Signaling and Anti-Inflammatory Actions

Zhang¹,

Xie²,

Leung³

2018

Cell Physiol Biochem

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Background/Aims: Islet metabolic disorder and inflammation contribute to the pathogenesis and progression of type 2 diabetes mellitus (T2DM). Irisin is a recently identified adipomyokine with protective effects on metabolic homeostasis and inflammation-suppressing effects in hepatic and vascular cells. The present study examined the effects of irisin on lipid metabolism and inflammation in β cells under glucolipotoxic conditions. Methods: Rat INS-1E β cells and islets isolated from C57BL/6 mice were incubated in glucolipotoxic conditions with or without irisin. Intracellular lipid contents and lipogenic gene expression were determined by enzymatic colorimetric assays and real-time PCR, respectively. Inflammatory status was evidenced by Western blot analysis for the phosphorylation of nuclear factor-κB (NF-κB) p65 and real-time PCR analysis for the expression of pro-inflammatory genes. Results: Irisin reversed glucolipotoxicity-induced intracellular non-esterified fatty acid (NEFA) and triglyceride accumulation, suppressed associated elevations in lipogenic gene expression, and phosphorylated acetyl-CoA-carboxylase (ACC) in INS-1E cells. These demonstrated effects were dependent on irisin-activated adenosine monophosphate-activated protein kinase (AMPK). Meanwhile, AMPK signaling mediated the protective effects of irisin on INS-1E cell insulin secretory ability and survival as well. Additionally, irisin inhibited phosphorylation of NF-κB p65 while decreasing the expression of pro-inflammatory genes in INS-1E cells under glucolipotoxic conditions. Moreover, irisin also improved insulin secretion, inhibited apoptosis, and restored β-cell function-related gene expression in isolated mouse islets under glucolipotoxic conditions. Conclusion: Irisin attenuated excessive lipogenesis in INS-1E cells under glucolipotoxic state through activation of AMPK. Irisin also suppressed overnutrition-induced inflammation in INS-1E cells. Our findings implicate irisin as a promising therapeutic target for the treatment of islet lipid metabolic disorder and islet inflammation in T2DM.

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Section: Discussionmentioning

confidence: 99%

Irisin Ameliorates Glucolipotoxicity-Associated β-Cell Dysfunction and Apoptosis via AMPK Signaling and Anti-Inflammatory Actions

Zhang¹,

Xie²,

Leung³

2018

Cell Physiol Biochem

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“…Although not extensively studied in muscle, FAS regulation involves insulin signaling, the induction of the transcription factor SREBP1c (also known as SREBF1), and other factors (48). In humans, skeletal muscle expression of SREBP1c is highest in individuals that are most insulin resistant (49).…”

Section: Methodsmentioning

confidence: 99%

Muscle lipogenesis balances insulin sensitivity and strength through calcium signaling

Funai

Song²,

Li³

et al. 2013

J. Clin. Invest.

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125

148

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Exogenous dietary fat can induce obesity and promote diabetes, but endogenous fat production is not thought to affect skeletal muscle insulin resistance, an antecedent of metabolic disease. Unexpectedly, the lipogenic enzyme fatty acid synthase (FAS) was increased in the skeletal muscle of mice with diet-induced obesity and insulin resistance. Skeletal muscle-specific inactivation of FAS protected mice from insulin resistance without altering adiposity, specific inflammatory mediators of insulin signaling, or skeletal muscle levels of diacylglycerol or ceramide. Increased insulin sensitivity despite high-fat feeding was driven by activation of AMPK without affecting AMP content or the AMP/ATP ratio in resting skeletal muscle. AMPK was induced by elevated cytosolic calcium caused by impaired sarco/endoplasmic reticulum calcium ATPase (SERCA) activity due to altered phospholipid composition of the sarcoplasmic reticulum (SR), but came at the expense of decreased muscle strength. Thus, inhibition of skeletal muscle FAS prevents obesity-associated diabetes in mice, but also causes muscle weakness, which suggests that mammals have retained the capacity for lipogenesis in muscle to preserve physical performance in the setting of disrupted metabolic homeostasis.

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“…These data suggest differential posttranscriptional regulation of FASN among species due to (1) higher translation repression or degradation of mRNA in cows, which affects FASN protein synthesis and mRNA stability (Semenkovich et al, 1993) and may involve microRNA such as miR-145 (Wang et al, 2017) and miR-24 (Wang et al, 2015) that target FASN mRNA; (2) different ubiquitination of lysine or phosphorylation in sites of the protein sequence affecting protein activity (Wakil et al, 1989;Jensen-Urstad and Semenkovich, 2012); or (3) other mechanisms. In addition to the multifunctional enzyme FAS, the biosynthesis of de novo FA requires considerable amounts of reducing equivalents in the form of NADPH.…”

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confidence: 99%

Comparison of mammary lipid metabolism in dairy cows and goats fed diets supplemented with starch, plant oil, or fish oil

Bernard

Toral

Chilliard

2017

Journal of Dairy Science

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A direct comparison of cow and goat performance and milk fatty acid (FA) responses to diets known to induce milk fat depression in the bovine has suggested interspecies differences in rumen and mammary lipid metabolism. Thus, this study was conducted to infer some potential mechanisms responsible for the differences in mammary lipogenesis due to diet and ruminant species. To meet this objective, 12 cows and 15 goats were fed a basal diet (control), a similar diet supplemented with 2.2% fish oil (FO), or a diet containing 5.3% sunflower oil and additional starch (+38%; SOS) according to a 3 × 3 Latin square design with 26-d experimental periods. Milk yield, milk composition, FA profile, and FA secretion were measured. On the last day of each period, the mRNA abundance of 19 key genes in mammary metabolism or the enzyme activity or both were measured in mammary tissue sampled by biopsy or at slaughter or both. The results show significant differences in the response of cows and goats to the dietary treatments. In cows, milk fat content and yield were lowered by FO and SOS (−31%), whereas only FO decreased milk fat content in goats (−21%) compared with the control. In cows and to a lesser extent in goats, FO and SOS decreased the secretion of C16 FA output (mmol/kg of BW). However, SOS increased the secretion of >C16 FA in goats. These changes in milk fat content and FA secretion were not associated with modifications in mammary expression or the activity of 19 proteins involved in the major lipogenic pathways. This absence of variation may be attributable to posttranscriptional regulation for these genes or related to the time of sampling of the mammary tissue relative to the previous meal and milking. Otherwise, the abundances of 15 mRNA among the 19 encoding for genes involved in lipid metabolism in the mammary gland were different among species, with 9 more abundant in cows (FASN, FADS1, SCD1, GPD1, LALBA, SREBF1, LXRA, PPARA, and PPARG1) and 6 more abundant in goats (G6PD, GPAM, SCD5, XDH, CSN2, and SP1). Similarly, a significant effect of the species was observed in the 4 enzyme activities measured; glycerol-3-phosphate dehydrogenase and malic enzyme were higher in cows, and FA synthase and glucose-6-phosphate dehydrogenase activities were higher in goats. In conclusion, the differences between cow and goat performance and milk FA responses to the FO and SOS treatments were not related to changes in the measured mammary lipogenic gene expression. Furthermore, the data provide evidence that the major mammary lipogenic pathways differ between the caprine and the bovine, whose biological significance remains to be unraveled.

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Fatty acid synthase and liver triglyceride metabolism: Housekeeper or messenger?

Cited by 322 publications

References 83 publications

Irisin Ameliorates Glucolipotoxicity-Associated β-Cell Dysfunction and Apoptosis via AMPK Signaling and Anti-Inflammatory Actions

Irisin Ameliorates Glucolipotoxicity-Associated β-Cell Dysfunction and Apoptosis via AMPK Signaling and Anti-Inflammatory Actions

Muscle lipogenesis balances insulin sensitivity and strength through calcium signaling

Comparison of mammary lipid metabolism in dairy cows and goats fed diets supplemented with starch, plant oil, or fish oil

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