Effects of Daily Raspberry Consumption on Immune-Metabolic Health in Subjects at Risk of Metabolic Syndrome: A Randomized Controlled Trial.

Consumption of red raspberries has been reported to exert acute beneficial effects on postprandial glycemia, insulinemia, triglyceridemia, and cytokine levels in metabolically disturbed subjects. In a two-arm parallel-group, randomized, controlled trial, 59 subjects with overweight or abdominal obesity and with slight hyperinsulinemia or hypertriglyceridemia were randomized to consume 280 g/day of frozen raspberries or to maintain their usual diet for 8 weeks. Primary analyses measured metabolic differences between the groups. Secondary analyses performed with omics tools in the intervention group assessed blood gene expression and plasma metabolomic changes following the raspberry supplementation. The intervention did not significantly affect plasma insulin, glucose, inflammatory marker concentrations, nor blood pressure. Following the supplementation, 43 genes were differentially expressed, and several functional pathways were enriched, a major portion of which were involved in the regulation of cytotoxicity, immune cell trafficking, protein signal transduction, and interleukin production. In addition, 10 serum metabolites were found significantly altered, among which ß-alanine, trimethylamine N-oxide, and bioactive lipids. Although the supplementation had no meaningful metabolic effects, these results highlight the impact of a diet rich in raspberry on the immune function and phospholipid metabolism, thus providing novel insights into potential immune-metabolic pathways influenced by regular raspberry consumption.

Diurnal Rhythmicity Programs of Microbiota and Transcriptional Oscillation of Circadian Regulator, NFIL3.

Circadian rhythms are a very exquisite mechanism to influence on transcriptional levels and physiological activities of various molecules that affect cell metabolic pathways. Long-term alteration of circadian rhythms increases the risk of cardiovascular diseases, hypertension, hypertriglyceridemia, and metabolic syndrome. A drastic change in dietary patterns can affect synchronizing the circadian clock within the metabolic system. Therefore, the interaction between the host and the bacterial community colonizing the mammalian gastrointestinal tract has a great impact on the circadian clock in diurnal programs. Here, we propose that the microbiota regulates body composition through the transcriptional oscillation of circadian regulators. The transcriptional regulator, NFIL3 (also called E4BP4) is a good example. Compositional change of the commensal bacteria influences the rhythmic expression of NFIL3 in the epithelium, which subsequently controls obesity and insulin resistance. Therefore, control of circadian regulators would be a promising therapeutic target for metabolic diseases.

Chylomicronemia from GPIHBP1 autoantibodies.

Some cases of chylomicronemia are caused by autoantibodies against glycosylphosphatidylinositol-anchored HDL binding protein 1 (GPIHBP1), an endothelial cell protein that shuttles LPL to the capillary lumen. GPIHBP1 autoantibodies prevent binding and transport of LPL by GPIHBP1, thereby disrupting the lipolytic processing of triglyceride-rich lipoproteins. Here, we review the "GPIHBP1 autoantibody syndrome" and summarize clinical and laboratory findings in 22 patients. All patients had GPIHBP1 autoantibodies and chylomicronemia, but we did not find a correlation between triglyceride levels and autoantibody levels. Many of the patients had a history of pancreatitis, and most had clinical and/or serological evidence of autoimmune disease. IgA autoantibodies were present in all patients, and IgG4 autoantibodies were present in 19 of 22 patients. Patients with GPIHBP1 autoantibodies had low plasma LPL levels, consistent with impaired delivery of LPL into capillaries. Plasma levels of GPIHBP1, measured with a monoclonal antibody-based ELISA, were very low in 17 patients, reflecting the inability of the ELISA to detect GPIHBP1 in the presence of autoantibodies (immunoassay interference). However, GPIHBP1 levels were very high in five patients, indicating little capacity of their autoantibodies to interfere with the ELISA. Recently, several GPIHBP1 autoantibody syndrome patients were treated successfully with rituximab, resulting in the disappearance of GPIHBP1 autoantibodies and normalization of both plasma triglyceride and LPL levels. The GPIHBP1 autoantibody syndrome should be considered in any patient with newly acquired and unexplained chylomicronemia.

Therapeutic approaches in hypertriglyceridemia-induced acute pancreatitis: A literature review of available therapies and case series.

Hypertriglyceridemia-induced acute pancreatitis (HGAP) is the third most common etiology of acute pancreatitis. HGAP can be attributed to genetic disturbances in triglyceride metabolism or multiple secondary causes. Here, we presented three cases for HGAP and explored different therapeutic approaches for treating HGAP. A case series of three patients who presented with HGAP and underwent different therapeutic approaches was conducted. The first patient was a 37-year-old male who presented with nonsevere HGAP; he was treated with conservative therapy with insulin and heparin infusion, which resulted in clinical and laboratory improvement. The second patient was a 64-year-old male with human immunodeficiency virus on multiple highly active antiretroviral therapy. He presented with severe HGAP and multiorgan failure. After initiation of therapeutic plasma exchange, his HGAP resolved. The third patient was a 28-year-old male who presented with recurrent episodes of HGAP; his conservative therapy failed and was eventually escalated to therapeutic plasma exchange (TPE). HGAP can be attributed to genetic disturbances of lipid or secondary etiologies. A nonsevere form of HGAP can be managed with conventional therapy including insulin and heparin; however, severe HGAP may require TPE.

Extreme hypertriglyceridemia: Genetic diversity, pancreatitis, pregnancy, and prevalence.

BACKGROUND: Triglyceride (TG) concentrations >2000 mg/dL are extremely elevated and increase the risk of pancreatitis. OBJECTIVES: We characterized five cases and two kindreds and ascertained prevalence in a reference laboratory population. METHODS: Plasma lipids and DNA sequences of LPL, GPIHBP1, APOA5, APOC2, and LMF1 were determined in cases and two kindreds. Hypertriglyceridemia prevalence was assessed in 440,240 subjects. RESULTS: Case 1 (female, age 28 years) had TG concentrations >2000 mg/dL and pancreatitis since infancy. She responded to diet and medium-chain triglycerides, but not medications. During two pregnancies, she required plasma exchange for TG control. She was a compound heterozygote for a p.G236Gfs*15 deletion and a p.G215E missense mutation at LPL, as was one sister with hypertriglyceridemia and pancreatitis during pregnancy. Her father was heterozygous for the deletion and had hypertriglyceridemia and recurrent pancreatitis. Other family members had either the missense mutation or the deletion, and had hypertriglyceridemia but no pancreatitis. In kindred 2, three preschool children had severe hypertriglyceridemia and were homozygous for a GPIHBP1 p.T108R missense mutation. Case 5 (male, age 43 years) presented with pancreatitis and TG levels >5000 mg/dL and had heterozygous GPIHBP1 p.G175R and APOC2 intron 2-4G>C mutations. On diet, fenofibrate, fish oil, and atorvastatin, his TG concentration was 2526 mg/dL, but normalized to <100 mg/dL with added pioglitazone. In our population study, 60 subjects (0.014%) of 440,240 had TG concentrations >2000 mg/dL, and 66.7% were diabetic and had elevated insulin levels. CONCLUSIONS: Extreme hypertriglyceridemia is rare (0.014%); and during pregnancy, it may require plasma exchange.

Case Report of Acquired Generalized Lipodystrophy Associated With Common Variable Immunodeficiency.

Context: Acquired generalized lipodystrophy (AGL), a rare disorder characterized by loss of subcutaneous adipose tissue, is estimated to occur in association with autoimmune diseases in ~25% of the cases. Common variable immunodeficiency (CVI) is a condition known for its strong association with autoimmune diseases often occurring with negative autoantibodies. To the best of our knowledge, we describe the first known case of AGL in a patient with CVI. Case Description: A 24-year-old man was referred to our center with hyperglycemia, hypertriglyceridemia, hepatomegaly, and a clear pattern of generalized fat loss. AGL had been diagnosed on the basis of the clinical and laboratory findings. Because of the presence of associated hypogammaglobulinemia, a diagnosis of CVI was subsequently established. Conclusions: We propose that AGL be added to the list of possible diseases associated with CVI and, owing to the similar clinical presentation with type 1 diabetes mellitus, be included in the differential diagnosis of this condition, which is present in 1.5% of patients with CVI.

Anti-sense oligonucleotide therapies for the treatment of hyperlipidaemia.

INTRODUCTION: Anti-sense oligonucleotide (ASO) therapies are a new development in clinical pharmacology offering greater specificity compared to small molecule inhibitors and the ability to target intracellular process' not susceptible to antibody-based therapies. AREAS COVERED: This article reviews the chemical biology of ASOs and related RNA therapeutics. It then reviews the data on their use to treat hyperlipidaemia. Data on mipomersen - an ASO to apolipoprotein B-100(apoB) licensed for treatment of homozygous familial hypercholesterolaemia (FH) is presented. Few effective therapies are available to reduce atehrogenic lipoprotein (a) levels. An ASO therapy to apolipoprotein(a) (ISIS Apo(a)Rx) specifically reduced lipoprotein (a) levels by up to 78%. Treatment options for patients with familial chylomicronaemia syndrome (lipoprotein lipase deficiency; LPLD) or lipodystrophies are highly limited and often inadequate. Volanesorsen, an ASO to apolipoprotein C-3, shows promise in the treatment of LPLD and severe hypertriglyceridaemia as it increases clearance of triglyceride-rich lipoproteins and can normalise triglycerides in these patients. EXPERT OPINION: The uptake of the novel ASO therapies is likely to be limited to selected niche groups or orphan diseases. These will include homozygous FH, severe heterozygous FH for mipomersen; LPLD deficiency and lipodystrophy syndromes for volanesorsen and treatment of patients with high elevated Lp(a) levels.

Pro-inflammatory chemokines CCL2, chemerin, IP-10 and RANTES in human serum during an oral lipid tolerance test.

BACKGROUND: There is a strong coincidence of obesity and a chronic state of modest inflammation. Secretion of pro-inflammatory cytokines from adipocytes and immune cells represents a key mechanism in this process and is affected by fatty acids. MATERIAL AND METHODS: A study cohort of 100 overnight fasted healthy volunteers underwent an oral lipid tolerance test (OLTT) by ingestion of 160ml of a protein- and sugar-free lipid emulsion of defined composition. Venal blood was drawn at 0h (fasting) and at 2, 4, and 6h after lipid ingestion. Subjects were characterized by anthropometric and standard laboratory parameters. Serum concentrations of CCL2, IP-10, chemerin, and RANTES were measured by enzyme-linked immunosorbent assay (ELISA). Murine 3T3-L1 adipocytes were stimulated with free fatty acids (FA) and with sex steroids and concentrations of CCL2 and chemerin in cell culture supernatants were measured by ELISA. RESULTS: A significant reduction of circulating CCL2, IP-10, and chemerin concentrations was observed as a consequence of triglyceride ingestion whereas RANTES levels were increased. CCL2 serum concentrations were positively correlated with resistin and visfatin levels and with LDL/HDL ratio and negatively with adiponectin. There were significant differences in chemerin and RANTES serum concentrations in female and male subjects. CCL2 secretion from 3T3-L1 adipocytes was inhibited by treatment with linoleic (LA) and oleic acid (OA) whereas chemerin secretion was induced. Chemerin release from 3T3-L1 adipocytes was inhibited by testosterone. CONCLUSIONS: Oral lipid loading is linked to reduced circulating pro-inflammatory chemokines CCL2, IP-10, and chemerin and to increased RANTES levels, suggesting that dietary lipids affect immune function.

Highly Active Antiretroviral Therapy (HAART)-Related Hypertriglyceridemia Is Associated With Failure of Recovery of CD14lowCD16+ Monocyte Subsets in AIDS Patients.

As cellular reservoirs, CD16 monocyte subsets play important roles in the progression of HIV infection. Previous studies have shown that highly active antiretroviral therapy (HAART) reduced the percentages of CD14CD16 monocyte subsets, but did not recover the percentages of CD14CD16 subsets. Eighty-four chronic HIV-infected, HAART-naïve individuals and 55 HIV-negative subjects (31 without hyperlipidemia and 24 with hypertriglyceridemia) were enrolled. Plasma HIV-1 RNA levels, CD4 T-cell counts, triglycerides, total cholesterol, high-density lipoprotein, and low-density lipoprotein were followed up for 48 weeks during HAART treatment in the longitudinal study. We found that mild hypertriglyceridemia in HIV-negative subjects and HIV-infected patients, naïve to HAART, did not affect the percentage of monocyte subsets. However, a failure of CD14CD16 subset recovery was observed in patients with HAART-related hypertriglyceridemia at 48 weeks. Thus, HAART-related hypertriglyceridemia altered homeostasis of monocyte subsets to antiviral therapy, which might further affect immune reconstitution.

Biliverdin reductase isozymes in metabolism.

The biliverdin reductase (BVR) isozymes BVRA and BVRB are cell surface membrane receptors with pleiotropic functions. This review compares, for the first time, the structural and functional differences between the isozymes. They reduce biliverdin, a byproduct of heme catabolism, to bilirubin, display kinase activity, and BVRA, but not BVRB, can act as a transcription factor. The binding motifs present in the BVR isozymes allow a wide range of interactions with components of metabolically important signaling pathways such as the insulin receptor kinase cascades, protein kinases (PKs), and inflammatory mediators. In addition, serum bilirubin levels have been negatively associated with abdominal obesity and hypertriglyceridemia. We discuss the roles of the BVR isozymes in metabolism and their potential as therapeutic targets.

Autoimmune severe hypertriglyceridemia induced by anti-apolipoprotein C-II antibody.

CONTEXT: Among type V hyperlipoproteinemias, only one-fourth of the patients have genetic defects in lipoprotein lipase (LPL) or in its associated molecules; the exact mechanism in other patients is usually unknown. OBJECTIVE: The aim of the study was to report a case of severe hypertriglyceridemia induced by anti-apolipoprotein (apo) C-II autoantibody and to clarify its pathogenesis. SUBJECT AND METHODS: A 29-year-old Japanese woman presented with severe persistent hypertriglyceridemia since the age of 20 years. The past history was negative for acute pancreatitis, eruptive xanthomas, or lipemia retinalis. LPL mass and activities were normal. Plasma apo C-II levels were extremely low, but no mutation was observed in APOC2. RESULTS: Apo C-II protein was detected in the serum by immunoprecipitation and Western blotting. Large amounts of IgG and IgM were incorporated with apo C-II protein coimmunoprecipitated by anti-apo C-II antibody. IgG, but not IgM, purified from the serum prevented interaction of apo C-II with lipid substrate and diminished LPL hydrolysis activity. CONCLUSION: We identified anti-apo C-II antibody in a myeloma-unrelated severe hypertriglyceridemic patient. In vitro analysis confirmed that the autoantibody disrupted the interaction between apo C-II and lipid substrate, suggesting the etiological role of anti-apo C-II antibody in severe hypertriglyceridemia in this patient.

Correlation between CD14+CD16++ monocytes in peripheral blood and hypertriglyceridemia after allograft renal transplantation.

BACKGROUND: Cardio-cerebrovascular diseases are key factors causing recipient the death after kidney transplantation (KT). Hypertriglyceridemia (HTG), a complication commonly occurring among KT patients, is a major risk factor for cardio-cerebrovascular diseases. The objective of this study was to examine the correlation between peripheral CD14+CD16++ monocytes in KT patients and blood lipids as well as factors affecting hyperglycemia, seeking to understand mechanisms of inflammatory immune reactions. METHODS: KT patients (n = 60) were divided into subjects with HTG (n = 35) versus without HTG (n = 25). A cohort of healthy participants (55 cases) was divided into the cases without (n = 30) versus with HTG (n = 25). The proportion of peripheral CD14+CD16 ++ monocytes was determined using flow cytometry and hematology, and biochemical indicators were measured by conventional methods. We correlated HTG with these indicators. RESULTS: The proportion of peripheral blood CD14+CD16++ monocytes among the renal transplant group was significantly lower (P < .05) than that of normal controls. The expression of CD14+CD16++ monocytes among transplant recipients positively correlated with triglycerides (R = 0.449 and R = 0.008, respectively). CONCLUSION: CD14+CD16++ mononcytes in peripheral blood may represent an independent risk factor for HTG after KT.

Increased levels of invariant natural killer T lymphocytes worsen metabolic abnormalities and atherosclerosis in obese mice.

Obesity is a chronic inflammatory state characterized by infiltration of adipose tissue by immune cell populations, including T lymphocytes. Natural killer T (NKT) cells, a specialized lymphocyte subset recognizing lipid antigens, can be pro- or anti-inflammatory. Their role in adipose inflammation continues to be inconclusive and contradictory. In obesity, the infiltration of tissues by invariant NKT (iNKT) cells is decreased. We therefore hypothesized that an excess iNKT cell complement might improve metabolic abnormalities in obesity. Vα14 transgenic (Vα14tg) mice, with increased iNKT cell numbers, on a LDL receptor-deficient (Ldlr(-/-)) background and control Ldlr(-/-) mice were placed on an obesogenic diet for 16 weeks. Vα14tg.Ldlr(-/-) mice gained 25% more weight and had increased adiposity than littermate controls. Transgenic mice also developed greater dyslipidemia, hyperinsulinemia, insulin resistance, and hepatic triglyceride accumulation. Increased macrophage Mac2 immunostaining and proinflammatory macrophage gene expression suggested worsened adipose inflammation. Concurrently, these mice had increased atherosclerotic lesion area and aortic inflammation. Thus, increasing the complement of iNKT cells surprisingly exacerbated the metabolic, inflammatory, and atherosclerotic features of obesity. These findings suggest that the reduction of iNKT cells normally observed in obesity may represent a physiological attempt to compensate for this inflammatory condition.

Krill oil versus fish oil in modulation of inflammation and lipid metabolism in mice transgenic for TNF-α.

PURPOSE: Biological effects of marine oils, fish oil (FO) and krill oil (KO), are mostly attributed to the high content of n-3 polyunsaturated fatty acids (n-3 PUFAs), predominantly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The study was aimed to investigate the influence of FO and KO on lipid homeostasis and inflammation in an animal model of persistent low-grade exposure to human tumor necrosis factor α (hTNF-α) and to evaluate whether these effects depend on the structural forms of EPA and DHA [triacylglycerols (TAG) vs. phospholipids]. METHODS: Male C57BL/6 hTNF-α mice were fed for 6 weeks a high-fat control diet (24.50 % total fats, w/w) or high-fat diets containing either FO or KO at similar doses of n-3 PUFAs (EPA: 5.23 vs. 5.39 wt%, DHA: 2.82 vs. 2.36 wt% of total fatty acids). RESULTS: We found that KO, containing bioactive n-3 PUFAs in the form of phospholipids, was capable of modulating lipid metabolism by lowering plasma levels of TAG and cholesterol and stimulating the mitochondrial and peroxisomal fatty acid ß-oxidation, as well as improving the overall carnitine turnover. Though the administration of FO was not as effective as KO in the lowering of plasma TAG, FO significantly improved the levels of all cholesterol classes in plasma. Except from the increase in the levels of IL-17 in FO-fed mice and a trend to decrease in MCP-1 levels in KO-fed animals, the levels of pro-inflammatory cytokines were not substantially different between treatment groups. CONCLUSION: Our findings demonstrate that FO and KO are comparable dietary sources of n-3 PUFAs. However, when quantitatively similar doses of n-3 PUFAs are administered, KO seems to have a greater potential to promote lipid catabolism. The effect of dietary oils on the levels of inflammatory markers in hTNF-α transgenic mice fed a high-fat diet needs further investigations.

Association between obesity, hypertriglyceridemia and low hepatitis B viral load.

OBJECTIVE: This study aimed to investigate the metabolic risk factors of high hepatitis B viral load. DESIGN: Large-scale, community-based cross-sectional study. SUBJECTS: A total of 3587 hepatitis B virus (HBV)-infected participants without liver cirrhosis at study entry were investigated. High HBV viral load was defined as a serum level 10(4) copies per ml for hepatitis B e antigen (HBeAg) seronegatives or 10(8) copies per ml for HBeAg seropositives. RESULTS: Among HBeAg seropositives (n=545), high HBV viral load was reversely associated with extreme obesity (odds ratio (OR), 0.30; 95% confidence interval (CI), 0.13-0.68; P=0.004) or central obesity (OR, 0.53; 95% CI, 0.34-0.82; P=0.004) after adjustment for gender, hypertriglyceridemia, hyperuricemia and history of hypertension. High HBV viral load remained significantly inversely associated with extreme obesity (OR, 0.17; 95% CI, 0.05-0.63; P=0.008) and central obesity (OR, 0.44; 95% CI, 0.25-0.78; P=0.005) in male HBeAg-seropositive participants in stratification analyses by gender. Among HBeAg seronegatives (n=3042), however, high HBV viral load was inversely associated with hypertriglyceridemia (OR, 0.74; 95% CI, 0.61-0.89, P=0.002) after adjustment for age, gender, high serum alanine aminotransferase level, and extreme obesity or central obesity. High HBV viral load was still inversely associated with hypertriglyceridemia in both female (OR, 0.70; 95% CI, 0.50-0.97; P=0.041) and male (OR, 0.75; 95% CI, 0.60-0.94; P=0.011) HBeAg-seronegative participants. CONCLUSION: Extreme obesity and central obesity were associated with a low prevalence of high HBV viral load in HBeAg seropositives, especially in men; while hypertriglyceridemia was associated with a low prevalence of high viral load in HBeAg seronegatives in both women and men.

Adipocyte fatty acid binding protein: a novel adipokine involved in the pathogenesis of metabolic and vascular disease?

Adipocyte fatty acid binding protein (AFABP, also known as aP2 and FABP4) has recently been introduced as a novel fat-derived circulating protein. AFABP serum concentrations are positively correlated with markers of the metabolic syndrome and vascular disease in various cross-sectional and interventional studies. Furthermore, a small set of prospective studies indicates that high AFABP serum levels at baseline predict the risk for metabolic and vascular morbidity and mortality. Studies in Afabp (also known as Fabp4) knockout mice and AFABP inhibitor-treated animals suggest that total AFABP promotes insulin resistance, hypertriacylglycerolaemia and atherosclerosis by ligand/ligand delivery, as well as ligand-independent mechanisms. In contrast, the pathophysiological significance of circulating AFABP and the mechanisms leading to its release remain to be established. The current review summarises recent findings on the regulation and potential role of AFABP in metabolic and vascular disease.

Up-regulation of the complement system in subcutaneous adipocytes from nonobese, hypertriglyceridemic subjects is associated with adipocyte insulin resistance.

BACKGROUND: Dysfunctional adipose tissue plays an important role in the etiology of the metabolic syndrome, type 2 diabetes, and dyslipidemia. However, the molecular mechanisms underlying adipocyte dysfunction are incompletely understood. AIM: The aim of the study was to identify differentially regulated pathways in sc adipocytes of dyslipidemic subjects. METHODS: Whole-genome expression profiling was conducted on sc adipocytes from a discovery group of nine marginally overweight subjects with familial combined hyperlipidemia (FCHL) and nine controls of comparable body sizes as well as two independent confirmation groups. In this study, FCHL served as a model of familial insulin resistance and dyslipidemia, in the absence of frank obesity. RESULTS: Functional analyses and gene set enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes or a custom pathway database identified the complement system and complement regulators as one of the top up-regulated pathways in FCHL [false discovery rate (FDR) < 1E-30]. Higher adipocyte complement expression in FCHL was confirmed in the appropriate confirmation group. Higher complement gene expression was associated with lower adipocyte insulin receptor substrate-1 expression as marker of adipocyte insulin resistance, independent of age, sex, or disease status, and this association was corroborated in the two confirmation groups. Additionally, complement gene expression was associated with triglycerides in the discovery set and with triglycerides and/or waist circumference in the confirmation groups. Complement pathway up-regulation did not appear to be driven by hypertriglyceridemia because a 40% pharmacological reduction in triglycerides did not affect complement expression. CONCLUSIONS: These findings point to an up-regulation of a complement-related transcriptome in sc adipocytes under metabolically stressed conditions, even in the absence of overt obesity. Such up-regulation may subsequently influence downstream processes, including macrophage infiltration into adipose tissue and adipocyte insulin resistance.

Selective hepatic insulin resistance, VLDL overproduction, and hypertriglyceridemia.

Insulin plays a central role in regulating energy metabolism, including hepatic transport of very low-density lipoprotein (VLDL)-associated triglyceride. Hepatic hypersecretion of VLDL and consequent hypertriglyceridemia leads to lower circulating high-density lipoprotein levels and generation of small dense low-density lipoproteins characteristic of the dyslipidemia commonly observed in metabolic syndrome and type 2 diabetes mellitus. Physiological fluctuations of insulin modulate VLDL secretion, and insulin inhibition of VLDL secretion upon feeding may be the first pathway to become resistant in obesity that leads to VLDL hypersecretion. This review summarizes the role of insulin-related signaling pathways that determine hepatic VLDL production. Disruption in signaling pathways that reduce generation of the second messenger phosphatidylinositide (3,4,5) triphosphate downstream of activated phosphatidylinositide 3-kinase underlies the development of VLDL hypersecretion. As insulin resistance progresses, a number of pathways are altered that further augment VLDL hypersecretion, including hepatic inflammatory pathways. Insulin plays a complex role in regulating glucose metabolism, and it is not surprising that the role of insulin in VLDL and lipid metabolism will prove equally complex.