Explore the vast range of titles available.

Increased lipogenesis has been linked to an increased cancer risk and poor prognosis; however, the underlying mechanisms remain obscure. Here we show that phosphatidic acid phosphatase (PAP) lipin-1, which generates diglyceride precursors necessary for the synthesis of glycerolipids, interacts with and is a direct substrate of the Src proto-oncogenic tyrosine kinase. Obesity-associated microenvironmental factors and other Src-activating growth factors, including the epidermal growth factor, activate Src and promote Src-mediated lipin-1 phosphorylation on Tyr398, Tyr413 and Tyr795 residues. The tyrosine phosphorylation of lipin-1 markedly increases its PAP activity, accelerating the synthesis of glycerophospholipids and triglyceride. Alteration of the three tyrosine residues to phenylalanine (3YF-lipin-1) disables lipin-1 from mediating Src-enhanced glycerolipid synthesis, cell proliferation and xenograft growth. Re-expression of 3YF-lipin-1 in PyVT; Lpin1 −/− mice fails to promote progression and metastasis of mammary tumours. Human breast tumours exhibit increased p-Tyr-lipin-1 levels compared to the adjacent tissues. Importantly, statistical analyses show that levels of p-Tyr-lipin-1 correlate with tumour sizes, lymph node metastasis, time to recurrence and survival of the patients. These results illustrate a direct lipogenesis-promoting role of the pro-oncogenic Src, providing a mechanistic link between obesity-associated mitogenic signaling and breast cancer malignancy. Altered lipid metabolism has been associated with tumour malignancy, but underlying mechanisms are not clear. Here the authors show that proto-oncogene Src interacts and phosphorylates metabolic enzyme phosphatidic acid phosphatase LPIN1 (lipin-1) to promote growth and metastasis in breast cancer.

Skeletal muscle insulin resistance has been implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and atherogenic dyslipidemia associated with the metabolic syndrome by altering the distribution pattern of postprandial energy storage. We conducted a study to examine this hypothesis by reversing muscle insulin resistance with a single bout of exercise and measuring hepatic de novo lipogenesis and hepatic triglyceride synthesis after a carbohydrate-rich meal. We studied 12 healthy, young, lean, insulin resistant individuals in an interventional, randomized cross-over trial. The response to the ingestion of a carbohydrate-rich meal was studied at rest and after one 45-min bout of exercise on an elliptical trainer. Hepatic de novo lipogenesis was assessed by using 2H2O, and changes in glycogen and fat content in liver and muscle were measured by 13C and 1H magnetic resonance spectroscopy, respectively. Exercise resulted in a greater than threefold increase in postprandial net muscle glycogen synthesis (P < 0.001), reflecting improved muscle insulin responsiveness, and a ≈40% reduction (P < 0.05) in net hepatic triglyceride synthesis. These changes in whole body energy storage were accompanied by a ≈30% decrease in hepatic de novo lipogenesis (P < 0.01) and were independent of changes in fasting or postprandial plasma glucose and insulin concentrations. These data demonstrate that skeletal muscle insulin resistance is an early therapeutic target for the treatment and prevention of atherogenic dyslipidemia and NAFLD in young insulin resistant individuals who are prone to develop the metabolic syndrome and type 2 diabetes.

Aims/hypothesis The aim of this work was to investigate hepatic lipid metabolic processes possibly involved in the reduction of liver fat content (LF) observed in patients with type 2 diabetes after an isoenergetic diet enriched in monounsaturated fatty acids (MUFAs). Methods This is an ancillary analysis of a published study. In a parallel-group design, 30 men and eight women, aged 35–70 years, with type 2 diabetes and whose blood glucose was controlled satisfactorily (HbA 1c  < 7.5% [58 mmol/mol]) by diet or diet plus metformin, were randomised by MINIM software to follow either a high-carbohydrate/high-fibre/low-glycaemic index diet (CHO/fibre diet, n  = 20) or a high-MUFA diet (MUFA diet, n  = 18) for 8 weeks. The assigned diets were known for the participants and blinded for people doing measurements. Before and after intervention, LF was measured by 1 H-MRS (primary outcome) and indirect indices of de novo lipogenesis (DNL) (serum triacylglycerol palmitic:linoleic acid ratio), stearoyl-CoA desaturase activity (SCD-1) (serum triacylglycerol palmitoleic:palmitic acid ratio) and hepatic β-oxidation of fatty acids (β-hydroxybutyrate plasma concentrations) were measured. Results LF was reduced by 30% after the MUFA diet, as already reported. Postprandial β-hydroxybutyrate incremental AUC (iAUC) was significantly less suppressed after the MUFA diet ( n  = 16) (−2504 ± 4488 μmol/l × 360 min vs baseline −9021 ± 6489 μmol/l × 360 min) while it was unchanged after the CHO/fibre diet ( n  = 17) (−8168 ± 9827 μmol/l × 360 min vs baseline −7206 ± 10,005 μmol/l × 360 min, p  = 0.962) (mean ± SD, p  = 0.043). In the participants assigned to the MUFA diet, the change in postprandial β-hydroxybutyrate iAUC was inversely associated with the change in LF ( r  = −0.642, p  = 0.010). DNL and SCD-1 indirect indices did not change significantly after either of the dietary interventions. Conclusions/interpretation Postprandial hepatic oxidation of fatty acids is a metabolic process possibly involved in the reduction of LF by a MUFA-rich diet in patients with type 2 diabetes. Trial registration ClinicalTrials.gov NCT01025856 Funding The study was funded by Ministero Istruzione Università e Ricerca and Italian Minister of Health.

Acetyl-CoA carboxylase (ACC) catalyses the first step of de novo lipogenesis (DNL). Pharmacologic inhibition of ACC has been of interest for therapeutic intervention in a wide range of diseases. We demonstrate here that ACC and DNL are essential for platelet production in humans and monkeys, but in not rodents or dogs. During clinical evaluation of a systemically distributed ACC inhibitor, unexpected dose-dependent reductions in platelet count were observed. While platelet count reductions were not observed in rat and dog toxicology studies, subsequent studies in cynomolgus monkeys recapitulated these platelet count reductions with a similar concentration response to that in humans. These studies, along with ex vivo human megakaryocyte maturation studies, demonstrate that platelet lowering is a consequence of DNL inhibition likely to result in impaired megakaryocyte demarcation membrane formation. These observations demonstrate that while DNL is a minor quantitative contributor to global lipid balance in humans, DNL is essential to specific lipid pools of physiological importance. Pharmacological targeting of de novo lipogenesis is an attractive clinical target for a wide range of diseases. Kelly et al. report that de novo lipogenesis is essential for platelet production in primates, but not in dogs and rats.

Sebum production is key in the pathophysiology of acne, an extremely common condition, which when severe, may require treatment with isotretinoin, a known teratogen. Apart from isotretinoin and hormonal therapy, no agents are available to reduce sebum. Increasing our understanding of the regulation of sebum production is a milestone in identifying alternative therapeutic targets. Studies in sebocytes and human sebaceous glands indicate that agonists of peroxisome proliferator-activated receptors (PPARs) alter sebaceous lipid production. The goal of this study is to verify the expression and activity of PPARs in human skin and SEB-1 sebocytes and to assess the effects of PPAR ligands on sebum production in patients. To investigate the contribution of each receptor subtype to sebum production, lipogenesis assays were performed in SEB-1 sebocytes that were treated with PPAR ligands and isotretinoin. Isotretinoin significantly decreased lipogenesis, while the PPARα agonist-GW7647, PPARδ agonist-GW0742, PPARα/δ agonist-GW2433, PPARγ agonist rosiglitazone, and the pan-agonist-GW4148, increased lipogenesis. Patients treated with thiazolidinediones or fibrates had significant increases in sebum production (37 and 77%, respectively) when compared to age-, disease-, and sex-matched controls. These data indicate that PPARs play a role in regulating sebum production and that selective modulation of their activity may represent a novel therapeutic strategy for the treatment of acne.

De novo lipogenesis (DNL) is a complex and highly regulated process in which carbohydrates from circulation are converted into fatty acids that are then used for synthesizing either triglycerides or other lipid molecules. Dysregulation of DNL contributes to human diseases such as obesity, type 2 diabetes, and cardiovascular diseases. Thus, the lipogenic pathway may provide a new therapeutic opportunity for combating various pathological conditions that are associated with dysregulated lipid metabolism. Hepatic DNL has been well documented, but lipogenesis in adipocytes and its contribution to energy homeostasis and insulin sensitivity are less studied. Recent reports have gained significant insights into the signaling pathways that regulate lipogenic transcription factors and the role of DNL in adipose tissues. In this review, we will update the current knowledge of DNL in white and brown adipose tissues with the focus on transcriptional, post-translational, and central regulation of DNL. We will also summarize the recent findings of adipocyte DNL as a source of some signaling molecules that critically regulate energy metabolism.

Cancer cell growth requires fatty acids to replicate cellular membranes. The kinase Akt is known to up-regulate fatty acid synthesis and desaturation, which is carried out by the oxygen-consuming enzyme stearoyl-CoA desaturase (SCD)1. We used ¹³C tracers and lipidomics to probe fatty acid metabolism, including desaturation, as a function of oncogene expression and oxygen availability. During hypoxia, flux from glucose to acetyl-CoA decreases, and the fractional contribution of glutamine to fatty acid synthesis increases. In addition, we find that hypoxic cells bypass de novo lipogenesis, and thus, both the need for acetyl-CoA and the oxygen-dependent SCD1-reaction, by scavenging serum fatty acids. The preferred substrates for scavenging are phospholipids with one fatty acid tail (lysophospholipids). Hypoxic reprogramming of de novo lipogenesis can be reproduced in normoxic cells by Ras activation. This renders Ras-driven cells, both in culture and in allografts, resistant to SCD1 inhibition. Thus, a mechanism by which oncogenic Ras confers metabolic robustness is through lipid scavenging.

Autophagy has been associated with oncogenesis with one of its emerging key functions being its contribution to the metabolism of tumors. Therefore, deciphering the mechanisms of how autophagy supports tumor cell metabolism is essential. Here, we demonstrate that the inhibition of autophagy induces an accumulation of lipid droplets (LD) due to a decrease in fatty acid β-oxidation, that leads to a reduction of oxidative phosphorylation (OxPHOS) in acute myeloid leukemia (AML), but not in normal cells. Thus, the autophagic process participates in lipid catabolism that supports OxPHOS in AML cells. Interestingly, the inhibition of OxPHOS leads to LD accumulation with the concomitant inhibition of autophagy. Mechanistically, we show that the disruption of mitochondria-endoplasmic reticulum (ER) contact sites (MERCs) phenocopies OxPHOS inhibition. Altogether, our data establish that mitochondria, through the regulation of MERCs, controls autophagy that, in turn finely tunes lipid degradation to fuel OxPHOS supporting proliferation and growth in leukemia.

Key Points Lipogenic genes are coordinately regulated at the transcriptional level during the fasting–feeding cycle and by circadian rhythms. Having common features at their promoter regions, lipogenic genes are coordinately regulated. Transcription factors such as upstream stimulatory factors (USFs), sterol regulatory element-binding protein 1C (SREBP1C), liver X receptors (LXRs) and carbohydrate-responsive element-binding protein (ChREBP) have crucial roles. Post-translational modifications of lipogenic transcription factors and co-regulators by hormones and nutrients are tightly regulated by several signalling pathways. Various kinases–phosphatases, including DNA-dependent protein kinase (DNA–PK), atypical protein kinase C (aPKC) and AKT–mTOR, and acetyltransferase–deacetylases such as p300, affect their function, stability and/or localization. Chromatin remodelling by histone acetylation and methylation, as well as recruitment of the lipoBAF complex, have crucial roles in lipogenic gene transcription. Dysregulation of lipogenesis can contribute to hepatosteatosis, which is associated with obesity and insulin resistance. Furthermore, persistent lipogenesis during insulin resistance may occur, owing to nutrient fluxes to the liver. Glucose from excess dietary carbohydrate is converted to fatty acids in the liver through de novo lipogenesis. Lipogenic genes have common features in their promoters and are coordinately regulated at the transcriptional level. Recent insights have been gained into the signalling pathways that regulate key transcription factors such as USFs, SREBP1C, LXRs and ChREBP. Fatty acid and fat synthesis in the liver is a highly regulated metabolic pathway that is important for very low-density lipoprotein (VLDL) production and thus energy distribution to other tissues. Having common features at their promoter regions, lipogenic genes are coordinately regulated at the transcriptional level. Transcription factors, such as upstream stimulatory factors (USFs), sterol regulatory element-binding protein 1C (SREBP1C), liver X receptors (LXRs) and carbohydrate-responsive element-binding protein (ChREBP) have crucial roles in this process. Recently, insights have been gained into the signalling pathways that regulate these transcription factors. After feeding, high blood glucose and insulin levels activate lipogenic genes through several pathways, including the DNA-dependent protein kinase (DNA-PK), atypical protein kinase C (aPKC) and AKT–mTOR pathways. These pathways control the post-translational modifications of transcription factors and co-regulators, such as phosphorylation, acetylation or ubiquitylation, that affect their function, stability and/or localization. Dysregulation of lipogenesis can contribute to hepatosteatosis, which is associated with obesity and insulin resistance.

mTORC2 phosphorylates AKT in a hydrophobic motif site that is a biomarker of insulin sensitivity. In brown adipocytes, mTORC2 regulates glucose and lipid metabolism, however the mechanism has been unclear because downstream AKT signaling appears unaffected by mTORC2 loss. Here, by applying immunoblotting, targeted phosphoproteomics and metabolite profiling, we identify ATP-citrate lyase (ACLY) as a distinctly mTORC2-sensitive AKT substrate in brown preadipocytes. mTORC2 appears dispensable for most other AKT actions examined, indicating a previously unappreciated selectivity in mTORC2-AKT signaling. Rescue experiments suggest brown preadipocytes require the mTORC2/AKT/ACLY pathway to induce PPAR-gamma and establish the epigenetic landscape during differentiation. Evidence in mature brown adipocytes also suggests mTORC2 acts through ACLY to increase carbohydrate response element binding protein (ChREBP) activity, histone acetylation, and gluco-lipogenic gene expression. Substrate utilization studies additionally implicate mTORC2 in promoting acetyl-CoA synthesis from acetate through acetyl-CoA synthetase 2 (ACSS2). These data suggest that a principal mTORC2 action is controlling nuclear-cytoplasmic acetyl-CoA synthesis. mTORC2 activates Akt, a regulator of cell growth and metabolism, however, the role of mTORC2 in adipocytes is incompletely understood. Here the authors report that a mTORC2-Akt axis specifically activates ACLY to promote lipid synthesis and histone acetylation during brown adipocyte differentiation.