Chronic O-GlcNAcylation and Diabetic Cardiomyopathy: The Bitterness of Glucose

Type 2 diabetes (T2D) is a major risk factor for heart failure. Diabetic cardiomyopathy (DC) is characterized by diastolic dysfunction and left ventricular hypertrophy. Epidemiological data suggest that hyperglycaemia contributes to the development of DC. Several cellular pathways have been implicated in the deleterious effects of high glucose concentrations in the heart: oxidative stress, accumulation of advanced glycation end products (AGE), and chronic hexosamine biosynthetic pathway (HBP) activation. In the present review, we focus on the effect of chronic activation of the HBP on diabetic heart function. The HBP supplies N-acetylglucosamine moiety (O-GlcNAc) that is O-linked by O-GlcNAc transferase (OGT) to proteins on serine or threonine residues. This post-translational protein modification modulates the activity of the targeted proteins. In the heart, acute activation of the HBP in response to ischaemia-reperfusion injury appears to be protective. Conversely, chronic activation of the HBP in the diabetic heart affects Ca2+ handling, contractile properties, and mitochondrial function and promotes stress signaling, such as left ventricular hypertrophy and endoplasmic reticulum stress. Many studies have shown that O-GlcNAc impairs the function of key protein targets involved in these pathways, such as phospholamban, calmodulin kinase II, troponin I, and FOXO1. The data show that excessive O-GlcNAcylation is a major trigger of the glucotoxic events that affect heart function under chronic hyperglycaemia. Supporting this finding, pharmacological or genetic inhibition of the HBP in the diabetic heart improves heart function. In addition, the SGLT2 inhibitor dapagliflozin, a glucose lowering agent, has recently been shown to lower cardiac HBP in a lipodystophic T2D mice model and to concomitantly improve the diastolic dysfunction of these mice. Therefore, targeting cardiac-excessive O-GlcNAcylation or specific target proteins represents a potential therapeutic option to treat glucotoxicity in the diabetic heart

Identification of novel APOB mutations by targeted next-generation sequencing for the molecular diagnosis of familial hypobetalipoproteinemia

International audienceFamilial hypobetalipoproteinemia (FHBL) is a co-dominant disorder characterized by decreased plasma levels of LDL-cholesterol and apolipoprotein B (ApoB). Currently, genetic diagnosis in FHBL relies largely on Sanger sequencing to identify APOB and PCSK9 gene mutations and on western blotting to detect truncated ApoB species

Seipin regulates ER-lipid droplet contacts and cargo delivery

Seipin is an endoplasmic reticulum (ER) membrane protein implicated in lipid droplet (LD) biogenesis and mutated in severe congenital lipodystrophy (BSCL2). Here, we show that seipin is stably associated with nascent ER-LD contacts in human cells, typically via one mobile focal point per LD Seipin appears critical for such contacts since ER-LD contacts were completely missing or morphologically aberrant in seipin knockout and BSCL2 patient cells. In parallel, LD mobility was increased and protein delivery from the ER to LDs to promote LD growth was decreased. Moreover, while growing LDs normally acquire lipid and protein constituents from the ER, this process was compromised in seipin-deficient cells. In the absence of seipin, the initial synthesis of neutral lipids from exogenous fatty acid was normal, but fatty acid incorporation into neutral lipids in cells with pre-existing LDs was impaired. Together, our data suggest that seipin helps to connect newly formed LDs to the ER and that by stabilizing ER-LD contacts seipin facilitates the incorporation of protein and lipid cargo into growing LDs in human cells.Peer reviewe

Not Enough Fat: Mouse Models of Inherited Lipodystrophy

International audienceLipodystrophies belong to the heterogenous group of syndromes in which the primary defect is a generalized or partial absence of adipose tissue, which may be congenital or acquired in origin. Lipodystrophy should be considered in patients manifesting the combination of insulin resistance (with or without overt diabetes), dyslipidemia and fatty liver. Lipodystrophies are classified according to the etiology of the disease (genetic or acquired) and to the anatomical distribution of adipose tissue (generalized or partial). The mechanism of adipose tissue loss is specific to each syndrome, depending on the biological function of the mutated gene. Mice models, together with cellular studies have permitted clarification of the mechanisms by which human mutations deeply compromise adipocyte homeostasis. In addition, rodent models have proven to be crucial in deciphering the cardiometabolic consequences of the lack of adipose tissue such as NAFLD, muscle insulin resistance and cardiomyopathy. More precisely, tissue-specific transgenic and knockout mice have brought new tools to distinguish phenotypic traits that are the consequences of lipodystrophy from those that are cell-autonomous. In this review, we discuss the mice models of lipodystrophy including those of inherited human syndromes of generalized and partial lipodystrophy. We present how these models have demonstrated the central role of white adipose tissue in energetic homeostasis in general, including insulin sensitivity and lipid handling in particular. We underscore the differences reported with the human phenotype and discuss the limit of rodent models in recapitulating adipose tissue primary default. Finally, we present how these mice models have highlighted the function of the causative-genes and brought new insights into the pathophysiology of the cardiometabolic complications associated with lipodystrophy

Congenital Lipodystrophies and Dyslipidemias

International audienc

Syndromes d’insulino-resistance majeure : clinique et physiopathologie

La résistance à l’insuline est une anomalie métabolique fréquente. Elle joue un rôle important dans le syndrome métabolique (ou syndrome X), le diabète de type 2, l’obésité, les syndromes lipodystrophiques plus récemment individualisés survenant au cours des traitements antiviraux de la maladie VIH, et représente un risque cardio-vasculaire préoccupant. Cependant sa physiopathologie reste mal comprise dans ces situations. Les syndromes d’insulino-résistance majeure, bien que rares, permettent d’explorer les mécanismes des altérations de la transmission du message insulinique. Si des mutations du gène du récepteur de l’insuline ont ainsi été mises en évidence chez de rares patients, des altérations post-récepteur sont probablement en cause dans d’autres cas. De plus, le rôle de la répartition corporelle du tissu adipeux semble déterminant dans l’apparition de l’insulino-résistance, comme en témoigne le tableau clinique des lipodystrophies, congénitales ou acquises. Cependant, les deux syndromes lipodystrophiques dont la cause moléculaire est connue (la lipodystrophie familiale partielle de Dunnigan, due à des mutations du gène de la lamine A/C, et la lipodystrophie congénitale généralisée liée à des altérations de la seipine), ont encore une physiopathologie mystérieuse. En effet, la lamine A/C est une protéine nucléaire ubiquitaire, dont d’autres altérations conduisent à une myopathie squelettique et/ou cardiaque. Quant à la seipine, d’expression cérébrale prédominante, ses fonctions sont encore inconnues. Les avancées dans la compréhension de ces syndromes, en particulier les lipodystrophies qui peuvent être considérées comme des syndromes métaboliques caricaturaux, permettront probablement d’éclaicir la physiopathologie de l’insulino-résistance plus commune