SUMMARY The intestinal mucus barrier prevents pathogen invasion and maintains host-microbiota homeostasis. We show that fatty acid synthase (FAS), an insulin-responsive enzyme essential for de novo lipogenesis, helps maintain the mucus barrier by regulating Mucin 2, the dominant mucin in the colon and a central component of mucus. Inducible Cre recombinase-directed inactivation of the FAS gene in the colonic epithelium of mice is associated with disruptions in the intestinal mucus barrier as well as increased intestinal permeability, colitis, systemic inflammation, and changes in gut microbial ecology. FAS deficiency blocked the generation of palmitoylated Mucin 2, which must be S-palmitoylated at its N-terminus for proper secretion and function. Furthermore, a diabetic mouse model exhibited lower FAS levels and a decreased mucus layer, which could be restored with insulin treatment. Thus, the role of FAS in maintaining intestinal barrier function may explain the pathogenesis of intestinal inflammation in diabetes and other disorders.

Clear evidence indicates that cytokines, for instance, adipokines, hepatokines, inflammatory cytokines, myokines, and osteokines, contribute substantially to the development of abnormal glucose and lipid metabolism. Some cytokines play a positive role in metabolism action, while others have a negative metabolic role linking to the induction of metabolic dysfunction. The mechanisms involved are not fully understood, but are associated with lipid accumulation in organs and tissues, especially in the adipose and liver tissue, changes in energy metabolism, and inflammatory signals derived from various cell types, including immune cells. In this review, we describe the roles of certain cytokines in the regulation of metabolism and inter-organ signaling in regard to the pathophysiological aspects. Given the disease-related changes in circulating levels of relevant cytokines, these factors may serve as biomarkers for the early detection of metabolic disorders. Moreover, based on preclinical studies, certain cytokines that can induce improvements in glucose and lipid metabolism and immune response may emerge as novel targets of broader and more efficacious treatments and prevention of metabolic disease.

Fatty acid metabolism is perturbed in atherosclerotic lesions, but whether it affects lesion formation is unknown. To determine whether fatty acid synthesis affects atherosclerosis, we inactivated fatty-acid synthase (FAS) in macrophages of apoEdeficient mice. Serum lipids, body weight, and glucose metabolism were the same in FAS knock-out in macrophages (FASKOM) and control mice, but blood pressure was lower in FASKOM animals. Atherosclerotic extent was decreased 20 -40% in different aortic regions of FASKOM as compared with control mice on Western diets. Foam cell formation was diminished in FASKOM as compared with wild type macrophages due to increased apoAI-specific cholesterol efflux and decreased uptake of oxidized low density lipoprotein. Expression of the anti-atherogenic nuclear receptor liver X receptor ␣ (LXR␣; Nr1h3) and its downstream targets, including Abca1, were increased in FASKOM macrophages, whereas expression of the potentially pro-atherogenic type B scavenger receptor CD36 was decreased. Peroxisome proliferator-activated receptor ␣ (PPAR␣) target gene expression was decreased in FASKOM macrophages. PPAR␣ agonist treatment of FASKOM and wild type macrophages normalized PPAR␣ target gene expression as well as Nr1h3 (LXR␣). Atherosclerotic lesions were more extensive when apoE null mice were transplanted with LXR␣-deficient/FAS-deficient bone marrow as compared with LXR␣-replete/FAS-deficient marrow, consistent with antiatherogenic effects of LXR␣ in the context of FAS deficiency. These results show that macrophage FAS deficiency decreases atherosclerosis through induction of LXR␣ and suggest that FAS, which is induced by LXR␣, may generate regulatory lipids that cause feedback inhibition of LXR␣ in macrophages.

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Selenium exposure can induce liver insulin resistance and increased liver triglyceride concentrations in animals, which may link to an increased risk of nonalcoholic fatty liver disease (NAFLD). However, epidemiological studies investigating the association between elevated plasma selenium levels and NAFLD were not available. We aimed to investigate the association of selenium levels with the prevalence of NAFLD in Chinese adults. This was a cross-sectional study of 8550 Chinese adults aged 40 yr or older in Shanghai, China. A questionnaire, anthropometric measurements, and laboratory tests were conducted. NAFLD was diagnosed by hepatic ultrasound after the exclusion of alcohol abuse and other liver diseases. Plasma selenium concentration was assessed by inductively coupled plasma mass spectroscopy. The median concentration of plasma selenium was 213.0 μg/L. Elevated plasma selenium levels were associated with higher triglycerides, LDL-cholesterol, fasting plasma glucose, post-loading plasma glucose, A1c, HOMA-IR, as well as ALT, AST and γ-GT (all P < 0.05). The odds ratios were substantially higher for NAFLD (OR = 1.54, 95% CI 1.13–2.18) in the highest selenium quartile compared with those in the lowest quartile, after adjustment for potential cofounder. The results of this study provided epidemiological evidence that increased plasma selenium level is associated with elevated prevalence of NAFLD.

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Objectives: To investigate whether preprocedural high-dose atorvastatin decreases the incidence of contrast-induced nephropathy (CIN) and protects the renal function after emergency percutaneous coronary intervention (PCI). Methods: Statin-naive patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing emergency PCI (n = 161) randomly received atorvastatin (80 mg, n = 78, ATOR group) or placebo [n = 83, control (CON) group] followed by long-term atorvastatin (40 mg/day). The primary end point was incidence of CIN. Results: In the ATOR group, 2.6% of the patients developed CIN versus 15.7% in the CON group (p = 0.01). In the ATOR group, postprocedural serum creatinine was significantly lower (93.4 ± 17.1 vs. 112.6 ± 23.3 µmol/l at 48 h and 84.2 ± 14.2 vs. 95.3 ± 17.7 µmol/l at 72 h, both p < 0.0001) and in the CON group, peak serum cystatin C was lower (0.51 ± 0.14 vs. 0.61 ± 0.13 mg/l, p < 0.0001). Atorvastatin pretreatment was independently associated with a decreased risk of CIN (OR 0.084, 95% CI 0.015–0.462, p = 0.004). The proportion of alanine aminotransferase >3 × upper limit of the normal value within 1 month was 3.85 versus 1.20% (ATOR vs. CON group, p = 0.57). Conclusion: Preprocedural high-dose atorvastatin prevents CIN and protects the renal function in patients with acute STEMI undergoing emergency PCI.

These findings suggest that increased plasma MG level is associated with the elevation of HbA1c and MDA in newly diagnosed T2DM patients.