-GlcNAc transferase acts as a critical nutritional node for the control of liver homeostasis.

Background & Aims: -GlcNAcylation is a reversible post-translational modification controlled by the activity of two enzymes, -GlcNAc transferase (OGT) and -GlcNAcase (OGA). In the liver, -GlcNAcylation has emerged as an important regulatory mechanism underlying normal liver physiology and metabolic disease.

Methods: To address whether OGT acts as a critical hepatic nutritional node, mice with a constitutive hepatocyte-specific deletion of OGT (OGT) were generated and challenged with different carbohydrate- and lipid-containing diets.

Insulin resistance per se drives early and reversible dysbiosis-mediated gut barrier impairment and bactericidal dysfunction.

Objective: A common feature of metabolic diseases is their association with chronic low-grade inflammation. While enhanced gut permeability and systemic bacterial endotoxin translocation have been suggested as key players of this metaflammation, the mechanistic bases underlying these features upon the diabesity cascade remain partly understood.

Methods: Here, we show in mice that, independently of obesity, the induction of acute and global insulin resistance and associated hyperglycemia, upon treatment with an insulin receptor (IR) antagonist (S961), elicits gut hyperpermeability without triggering systemic inflammatory response.

Insulin activates hepatic Wnt/β-catenin signaling through stearoyl-CoA desaturase 1 and Porcupine.

The Wnt/β-catenin pathway plays a pivotal role in liver structural and metabolic homeostasis. Wnt activity is tightly regulated by the acyltransferase Porcupine through the addition of palmitoleate. Interestingly palmitoleate can be endogenously produced by the stearoyl-CoA desaturase 1 (SCD1), a lipogenic enzyme transcriptionally regulated by insulin.

A Specific ChREBP and PPARα Cross-Talk Is Required for the Glucose-Mediated FGF21 Response.

While the physiological benefits of the fibroblast growth factor 21 (FGF21) hepatokine are documented in response to fasting, little information is available on Fgf21 regulation in a glucose-overload context. We report that peroxisome-proliferator-activated receptor α (PPARα), a nuclear receptor of the fasting response, is required with the carbohydrate-sensitive transcription factor carbohydrate-responsive element-binding protein (ChREBP) to balance FGF21 glucose response. Microarray analysis indicated that only a few hepatic genes respond to fasting and glucose similarly to Fgf21.

Growth factor receptor binding protein 14 inhibition triggers insulin-induced mouse hepatocyte proliferation and is associated with hepatocellular carcinoma.

Unlabelled: Metabolic diseases such as obesity and type 2 diabetes are recognized as independent risk factors for hepatocellular carcinoma (HCC). Hyperinsulinemia, a hallmark of these pathologies, is suspected to be involved in HCC development. The molecular adapter growth factor receptor binding protein 14 (Grb14) is an inhibitor of insulin receptor catalytic activity, highly expressed in the liver.

Novel Grb14-Mediated Cross Talk between Insulin and p62/Nrf2 Pathways Regulates Liver Lipogenesis and Selective Insulin Resistance.

A long-standing paradox in the pathophysiology of metabolic diseases is the selective insulin resistance of the liver. It is characterized by a blunted action of insulin to reduce glucose production, contributing to hyperglycemia, while de novo lipogenesis remains insulin sensitive, participating in turn to hepatic steatosis onset. The underlying molecular bases of this conundrum are not yet fully understood.

Proteomic analysis of beta-catenin activation in mouse liver by DIGE analysis identifies glucose metabolism as a new target of the Wnt pathway.

The Wnt/beta-catenin signaling pathway has been increasingly implicated in liver development and physiology. Aberrant activation of this pathway is one of the major genetic events observed during the process of human HCC development. To gain insight into the mechanism underlying beta-catenin action in the liver, we conducted a quantitative differential proteomic analysis using 2-D DIGE combined with MS, in mice with liver-specific deletion of Apc resulting in acute activation of beta-catenin signaling (Apc(KOliv) mice).

S26948, a new specific peroxisome proliferator activated receptor gamma modulator improved in vivo hepatic insulin sensitivity in 48 h lipid infused rats.

We examined whether S26948, a new specific peroxisome proliferator activated receptor gamma modulator prevented insulin-resistance induced by a 48 h intralipid-infusion in normal rat (IL rats). The effect of S26948 (30 mg/kg) was compared to rosiglitazone (10 mg/kg). Rats were catheterized in the right jugular vein 4 days before the beginning of the 48 h lipid or saline infusions.

Involvement of ZIP/p62 in the regulation of PPARalpha transcriptional activity by p38-MAPK.

The peroxisome proliferator-activated receptor alpha (PPARalpha) belongs to the nuclear receptor family and plays a central role in the regulation of lipid metabolism, glucose homeostasis and inflammatory processes. In addition to its ligand-induced activation, PPARalpha is regulated by phosphorylation via ERK-MAPK, PKA and PKC. In this study we examined the effect of p38-MAPK on PPARalpha transcriptional activity.

Dual effect of the adapter growth factor receptor-bound protein 14 (grb14) on insulin action in primary hepatocytes.

Tight control of insulin action in liver is a crucial determinant for the regulation of energy homeostasis. Growth factor receptor-bound protein 14 (Grb14) is a molecular adapter, highly expressed in liver, which binds to the activated insulin receptor and inhibits its tyrosine kinase activity. The physiological role of Grb14 in liver metabolism was unexplored.

Fatty acids induce L-CPT I gene expression through a PPARalpha-independent mechanism in rat hepatoma cells.

Liver carnitine palmitoyl transferase (L-CPT) I is a key regulatory enzyme of long-chain fatty acid (LCFA) oxidation that ensures the first step of LCFA import into the mitochondrial matrix. In rat hepatocytes, we showed previously that L-CPT I gene expression was induced by LCFAs as well as by fibrates. The aim of this study was to determine whether LCFA-induced L-CPT I gene expression was mediated by PPARalpha.

Leptin: a potential marker of placental insufficiency.

To investigate placental leptin production in placental insufficiency, placental leptin production was measured in women with severe preeclampsia (group 1) and in normotensive pregnancies associated with intrauterine growth restriction (group 2), compared to controls (group 3). Placental leptin content was increased 3-fold in group 1 compared to group 2 (192.5.