No abstract

Intestinal flora (microbiota) have recently attracted attention among lipid and carbohydrate metabolism researchers. Microbiota metabolize resistant starches and dietary fibers through fermentation and decomposition, and provide short chain fatty acids (SCFAs) to the host. The major SCFAs acetates, propionate and butyrate, have different production ratios and physiological activities. Several receptors for SCFAs have been identified as the G-protein coupled receptor 41/free fatty acid receptor 3 (GPR41/FFAR3), GPR43/FFAR2, GPR109A, and olfactory receptor 78, which are present in intestinal epithelial cells, immune cells, and adipocytes, despite their expression levels differing between tissues and cell types. Many studies have indicated that SCFAs exhibit a wide range of functions from immune regulation to metabolism in a variety of tissues and organs, and therefore have both a direct and indirect influence on our bodies. This review will focus on SCFAs, especially butyrate, and their effects on various inflammatory mechanisms including atherosclerosis. In the future, SCFAs may provide new insights into understanding the pathophysiology of chronic inflammation, metabolic disorders, and atherosclerosis, and we can expect the development of novel therapeutic strategies for these diseases.

The relationship of gastric hypermotility to mucosal hemodynamics, lipid peroxidation and vascular permeability changes was investigated in the pathogenesis of indomethacin-induced gastric lesions in rats. Subcutaneous administration of indomethacin (25 mg/kg) produced an increase in both the amplitude and frequency of stomach contraction from 30 min after treatment, resulting in hemorrhagic damage 2 h later. Gastric mucosal blood flow measured by a Laser flowmetry showed oscillatory fluctuations under hypercontractile states: a decrease during contraction followed by an increase during relaxation. Mucosal lipid peroxidation and vascular permeability were significantly increased with time after indomethacin treatment, and these changes preceded the appearance of hemorrhagic damage. All these events were prevented when gastric hypermotility was inhibited by atropine or 16,16-dimethyl prostaglandin E₂. Pretreatment of the animals with allopurinol and hydroxyurea or continuous infusion of superoxide dismutase and dimethyl sulfoxide during a test period also attenuated these functional changes and mucosal lesions induced by indomethacin, without affecting the motility response. We conclude that oxygen free radicals may play a role in the development of mucosal lesions associated with gastric hypermotility in indomethacin-treated rats.

Aim: Paracrine interaction between macrophages and adipocytes in obese visceral fat tissues is thought to be a trigger of chronic inflammation. The immunomodulatory effect of the short chain fatty acid, butyric acid, has been demonstrated. We hypothesize that sodium butyrate (butyrate) attenuates inflammatory responses and lipolysis generated by the interaction of macrophages and adipocytes. Methods: Using contact or transwell co-culture methods with differentiated 3T3-L1 adipocytes and RAW264.7 macrophages, we investigated the effects of butyrate on the production of tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein 1 (MCP-1), interleukin 6 (IL-6), and the release of free glycerol, free fatty acids (FFAs) into the medium. We also examined the activity of nuclear factor-kappaB (NF-κB) and the phosphorylation of mitogen-activated protein kinases (MAPKs) in co-cultured macrophages, as well as lipase activity and expression in co-cultured adipocytes. Results: We found increased production of TNF-α, MCP-1, IL-6, and free glycerol, FFAs in the coculture medium, and butyrate significantly reduced them. Butyrate inhibited the phosphorylation of MAPKs, the activity of NF-κB in co-cultured macrophages, and suppressed lipase activity in co-cultured adipocytes. Lipase inhibitors significantly attenuated the production of TNF-α, MCP-1 and IL-6 in the co-culture medium as effectively as butyrate. Butyrate suppressed the protein production of adipose triglyceride lipase, hormone sensitive lipase, and fatty acid-binding protein 4 in co-cultured adipocytes. Pertussis toxin, which is known to block GPR41 completely, inhibited the antilipolysis effect of butyrate. Conclusion: Butyrate suppresses inflammatory responses generated by the interaction of adipocytes and macrophages through reduced lipolysis and inhibition of inflammatory signaling.

Recent epidemiologic studies have revealed that hypertriglyceridemia is associated with atherosclerosis independent of other coronary risk factors. However, it is difficult to select patients at high risk for coronary artery disease using only serum triglyceride levels compared with low-density lipoprotein cholesterol levels since multiple factors are associated with elevating triglycerides. Atherosclerotic diseases with high triglyceride levels can be found in patients with familial combined hyperlipidemia, diabetes mellitus, and metabolic syndrome, in which remnant lipoproteins accumulate in the circulating blood. Recent researches have paid attention to remnant lipoproteins as atherogenic particles with the development of methods for measuring remnant cholesterol levels and apolipoprotein B-48 levels directly from human serum. Measurement of these parameters in addition to serum triglycerides may help to distinguish high-risk patients and enable us to prevent or suppress the progression of atherosclerotic diseases in those patients. However, questions remain to be answerd to evaluate the significance of remnant lipoproteins. Here, we focus on three issues: the underlying problems in measuring remnant lipoprotein cholesterol, the assessment of postprandial hyperlipidemia as an atherogenic condition, and finally a review of our experimental and clinical findings about the mechanisms by which remnant lipoproteins induce atherosclerosis.