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Rhythmic intraorgan communication coordinates environmental signals and the cell-intrinsic clock to maintain organ homeostasis. Hepatocyte-specific KO of core components of the molecular clock Rev-erb[alpha] and -[beta] (Reverb-hDKO) alters cholesterol and lipid metabolism in hepatocytes as well as rhythmic gene expression in nonparenchymal cells (NPCs) of the liver. Here, we report that in fatty liver caused by diet-induced obesity (DIO), hepatocyte SREBP cleavage-activating protein (SCAP) was required for Reverb-hDKO-induced diurnal rhythmic remodeling and epigenomic reprogramming in liver macrophages (LMs). Integrative analyses of isolated hepatocytes and LMs revealed that SCAP-dependent lipidomic changes in REV-ERB-depleted hepatocytes led to the enhancement of LM metabolic rhythms. Hepatocytic loss of REV-ERBa and [beta] (REV-ERBs) also attenuated LM rhythms via SCAP-independent polypeptide secretion. These results shed light on the signaling mechanisms by which hepatocytes regulate diurnal rhythms in NPCs in fatty liver disease caused by DIO., Introduction In almost all organisms, circadian rhythms, which regulate most biological processes and have strong ties to human health and disease, anticipate and adapt to daily environmental changes (1-3). The [...]

T follicular helper (T.sub.FH) cells are crucial for B cell-mediated humoral immunity.sup.1. Although transcription factors such as BCL6 drive the differentiation of T.sub.FH cells.sup.2,3, it is unclear whether and how post-transcriptional and metabolic programs enforce T.sub.FH cell programming. Here we show that the cytidine diphosphate (CDP)-ethanolamine pathway co-ordinates the expression and localization of CXCR5 with the responses of T.sub.FH cells and humoral immunity. Using in vivo CRISPR-Cas9 screening and functional validation in mice, we identify ETNK1, PCYT2, and SELENOI--enzymes in the CDP-ethanolamine pathway for de novo synthesis of phosphatidylethanolamine (PE)--as selective post-transcriptional regulators of T.sub.FH cell differentiation that act by promoting the surface expression and functional effects of CXCR5. T.sub.FH cells exhibit unique lipid metabolic programs and PE is distributed to the outer layer of the plasma membrane, where it colocalizes with CXCR5. De novo synthesis of PE through the CDP-ethanolamine pathway co-ordinates these events to prevent the internalization and degradation of CXCR5. Genetic deletion of Pcyt2, but not of Pcyt1a (which mediates the CDP-choline pathway), in activated T cells impairs the differentiation of T.sub.FH cells, and this is associated with reduced humoral immune responses. Surface levels of PE and CXCR5 expression on B cells also depend on Pcyt2. Our results reveal that phospholipid metabolism orchestrates post-transcriptional mechanisms for T.sub.FH cell differentiation and humoral immunity, highlighting the metabolic control of context-dependent immune signalling and effector programs. Enzymes in the cytidine diphosphate-ethanolamine metabolic pathway, which promotes de novo synthesis of phosphatidylethanolamine, are shown to act as post-transcriptional mediators of the differentiation of T follicular helper (T.sub.FH) cells, by regulating the chemokine receptor CXCR5., Author(s): Guotong Fu [sup.1] , Clifford S. Guy [sup.1] , Nicole M. Chapman [sup.1] , Gustavo Palacios [sup.1] , Jun Wei [sup.1] , Peipei Zhou [sup.1] , Lingyun Long [sup.1] [...]

Genetic variants near the TRIB1 gene are highly significantly associated with plasma lipid traits and coronary artery disease. While TRIB1 is likely causal of these associations, the molecular mechanisms are not well understood. Here we sought to investigate how TRIB1 influences low density lipoprotein cholesterol (LDL-C) levels in mice. Hepatocyte-specific deletion of Tribl ([Trib1.sup.[DELTA]hep]) in mice increased plasma cholesterol and apoB and slowed the catabolism of LDL-apoB due to decreased levels of LDL receptor (LDLR) mRNA and protein. Simultaneous deletion of the transcription factor CCAAT/enhancer-binding protein alpha (CEBP[alpha]) with TRIB1 eliminated the effects of TRIB1 on hepatic LDLR regulation and LDL catabolism. Using RNA-seq, we found that activating transcription factor 3 (Atf3) was highly upregulated in the livers of [Trib1.sup.[DELTA]hep] but not [Trib1.sup.[DELTA]hep] [Cebpa.sup.[DELTA]hep] mice. ATF3 has been shown to directly bind to the CEBP[alpha] protein, and to repress the expression of LDLR by binding its promoter. Blunting the increase of ATF3 in [Trib1.sup.[DELTA]hep] mice reduced the levels of plasma cholesterol and partially attenuated the effects on LDLR. Based on these data, we conclude that deletion of Trib1 leads to a posttranslational increase in CEBP[alpha], which increases ATF3 levels, thereby contributing to the downregulation of LDLR and increased plasma LDL-C., Introduction The TRIB1 gene, which encodes Tribbles homolog 1 protein (TRIB1), has been suggested as the causal effector transcript underlying the genome-wide association study (GWAS) signal at human chromosomal locus [...]

Insulin resistance and type 2 diabetes are associated with low levels of high- density lipoprotein cholesterol (HDL-C). The insulin-repressible FoxO transcription factors are potential mediators of the effect of insulin on HDL-C. FoxOs mediate a substantial portion of insulin-regulated transcription, and poor FoxO repression is thought to contribute to the excessive glucose production in diabetes. In this work, we show that mice with liver- specific triple FoxO knockout (L-FoxO1,3,4), which are known to have reduced hepatic glucose production, also have increased HDL-C. This was associated with decreased expression of the HDL-C clearance factors scavenger receptor class B type I (SR-BI) and hepatic lipase and defective selective uptake of HDL cholesteryl ester by the liver. The phenotype could be rescued by re- expression of SR-BI. These findings demonstrate that hepatic FoxOs are required for cholesterol homeostasis and HDL-mediated reverse cholesterol transport to the liver., Introduction The liver is a critical site for maintaining metabolic homeostasis. In hepatocytes, the forkhead transcription factors of the FoxO subfamily FoxO1, FoxO3, and FoxO4 (FoxOs) mediate a substantial portion [...]

The compensatory proliferation of insulin-producing [beta] cells is critical to maintaining glucose homeostasis at the early stage of type 2 diabetes. Failure of [beta] cells to proliferate results in hyperglycemia and insulin dependence in patients. To understand the effect of the interplay between [beta] cell compensation and lipid metabolism upon obesity and peripheral insulin resistance, we eliminated LDL receptor-related protein 1 (LRP1), a pleiotropic mediator of cholesterol, insulin, energy metabolism, and other cellular processes, in [beta] cells. Upon high-fat diet exposure, LRP1 ablation significantly impaired insulin secretion and proliferation of [beta] cells. The diminished insulin signaling was partly contributed to by the hypersensitivity to glucoseinduced, [Ca.sup.2+]-dependent activation of Erk and the mTORC1 effector p85 S6K1. Surprisingly, in LRP1-deficient islets, lipotoxic sphingolipids were mitigated by improved lipid metabolism, mediated at least in part by the master transcriptional regulator PPAR[gamma]2. Acute overexpression of PPAR[gamma]2 in [beta] cells impaired insulin signaling and insulin secretion. Elimination of Apbb2, a functional regulator of LRP1 cytoplasmic domain, also impaired [beta] cell function in a similar fashion. in summary, our results uncover the double-edged effects of intracellular lipid metabolism on [beta] cell function and viability in obesity and type 2 diabetes and highlight LRP1 as an essential regulator of these processes., Introduction At early stages of type 2 diabetes, [beta] cells increase insulin production by hyperplasia as a compensatory response to insulin resistance in peripheral tissues (I). At that stage, the [...]

Aberrant lipid metabolism promotes the development of skeletal muscle insulin resistance, but the exact identity of lipid-mediated mechanisms relevant to human obesity remains unclear. A comprehensive lipidomic analysis of primary myocytes from individuals who were insulin-sensitive and lean (LN) or insulin-resistant with obesity (OB) revealed several species of lysophospholipids (lyso-PLs) that were differentially abundant. These changes coincided with greater expression of lysophosphatidylcholine acyltransferase 3 (LPCAT3), an enzyme involved in phospholipid transacylation (Lands cycle). Strikingly, mice with skeletal muscle-specific knockout of LPCAT3 (LPCAT3-MKO) exhibited greater muscle lysophosphatidylcholine/phosphatidylcholine, concomitant with improved skeletal muscle insulin sensitivity. Conversely, skeletal muscle-specific overexpression of LPCAT3 (LPCAT3-MKI) promoted glucose intolerance. The absence of LPCAT3 reduced phospholipid packing of cellular membranes and increased plasma membrane lipid clustering, suggesting that LPCAT3 affects insulin receptor phosphorylation by modulating plasma membrane lipid organization. In conclusion, obesity accelerates the skeletal muscle Lands cycle, whose consequence might induce the disruption of plasma membrane organization that suppresses muscle insulin action., Introduction Type 2 diabetes is the 7th leading cause of death in the United States (1) and is a major risk factor for cardiovascular disease, the leading cause of death [...]

Obesity is characterized by aberrant fat accumulation. However, the intracellular signaling pathway that senses dietary fat and leads to fat storage remains elusive. Here, we have observed that the levels of histone deacetylase 6 (HDAC6) and the related family member HDAC10 are markedly reduced in adipose tissues of obese animals and humans. Mice with adipocyte-specific depletion of Hdac6 exhibited increased fat accumulation and reduced insulin sensitivity. In normal adipocytes, we found that reversal of P300/CBP-associated factor-induced (PCAF-induced) acetylation at K56 on cell death-inducing DFFA-like effector C (CIDEC, also known as FSP27) critically regulated lipid droplet fusion and lipid storage. Importantly, HDAC6 deacetylates CIDEC, leading to destabilization and reduced lipid droplet fusion. Accordingly, we observed elevated levels of CIDEC and its acetylated form in HDAC-deficient adipocytes as well as the adipose tissue of obese animals and humans. Fatty acids (FAs) prevented CIDEC deacetylation by promoting the dissociation of CIDEC from HDAC6, which resulted in increased association of CIDEC with PCAF on the endoplasmic reticulum. Control of CIDEC acetylation required the conversion of FAs to triacylglycerols. Thus, we have revealed a signaling axis that is involved in the coordination of nutrient availability, protein acetylation, and cellular lipid metabolic responses., Introduction Levels of protein acetylation have been shown to affect the activity of many proteins, and its aberrant regulation is linked to the development of cancer and metabolic diseases (1-4). [...]

BACKGROUND/OBJECTIVES: The aim was to examine the association of genetic risk scores (GRSs) of vitamin B12 and folate-associated variants with blood pressure and lipids. SUBJECTS/METHODS: The study included 12 532 adults from three population-based studies (Inter99, Health2006 and Dan-MONICA10) conducted in Denmark. GRSs were calculated by summarising the number of vitamin B12 and folate increasing alleles. Weighted GRSs were calculated as the sum of weights for each allele corresponding to genetic effects sizes. RESULTS: GRSs for serum vitamin B12 and folate were associated with serum vitamin B12 and folate, respectively. The [beta] coefficients (95% confidence interval (CI), P-value) for regression of log-transformed serum B12/folate on the weighted GRSs were 0.57 (0.54, 0.61), P < 0.001 and 0.85 (0.70, 1.01), P < 0.01. No associations were observed between the vitamin B12 GRSs and any of the blood pressure and lipid-related outcomes in the combined analyses. Increasing number of folate increasing alleles was associated with increased high-density lipoprotein (HDL) cholesterol concentrations ([beta] coefficient (95% CI, P-value) for regression of log-transformed HDL on the weighted GRSs, 0.081 (0.015, 0.148), P = 0.017), but not with blood pressure, triglyceride, and low-density lipoprotein and total cholesterol levels. CONCLUSIONS: GRSs were not associated with blood pressure and lipid levels, except for an association between the GRS for folate and HDL cholesterol. Further studies are needed to determine whether a causal association between folate and HDL cholesterol exists. European Journal of Clinical Nutrition (2016) 70, 613-619; doi: 10.1038/ejcn.2016.5; published online 24 February 2016, INTRODUCTION Despite a large number of epidemiological studies and randomised trials, there is still substantial controversy whether primary intervention with folic acid and vitamin B12 will lower cardiovascular disease (CVD) [...]

Abstract Energy homeostasis is subjected to a circadian control that synchronizes energy intake and expenditure. The transcription factor CLOCK, a key component of the molecular circadian clock, controls many kinds [...]

Vol 25, May 2002 * A controlled evaluation of staging dietary patterns to reduce the risk of diabetes in African-American women. W. Auslander, D. Haire-Joshu, C. Houston, C.-W. Rhee, and [...]