Integrative approach of pro-atheroma metabolism: the link between CHO, Fatty acids and inflammation

Factors determining SFA status and which thereby may ultimately contribute to chronic systemic low-grade inflammation and atherogenic lipidemia. A high fiber intake may increase gram-positive Firmicutes, resulting in a higher production of SCFAs, which together support gut integrity and may decrease LPS uptake [50] and [51]. High-fat diets, especially those rich in SFA, have been shown to increase LPS uptake in the gut [52] and [53], and LPS has been associated with inflammation via the activation of TLR4 [54]. A high CHO intake induces DNL and the production of SFA, while it also causes the sparing of dietary SFA. DNL is also stimulated by insulin resistance, the metabolic syndrome, nonalcoholic fatty liver disease/nonalcoholic steatohepatitis, high-GL foods, fructose and alcohol [49]. A high SFA status may cause inflammation via the activation of TLR4 and TLR2, ceramide production and formation of lipid rafts. More recently, fetuin A, a liver-derived circulating glycoprotein, has been shown to serve as an adaptor protein that directly links SFA to TLR4 activation and promote lipid-induced insulin resistance [55] and [56]. Excessive storage of SFA in adipose tissue may cause high free SFA during insulin resistance and upon fasting and thereby contribute to inflammation. Inflammation induces adaptations in metabolic (e.g., insulin resistance), hormonal (e.g., reduced insulin sensitivity, up-regulation of the hypothalamus–pituitary–adrenal axis, down-regulation of the hypothalamus–pituitary–gonadal axis) and nervous pathways (e.g., sympathetic nervous system activation), which are jointly meant for the reallocation of energy-rich nutrients that spare glucose for the brain and immune system and force other organs to use lipids for energy generation[14]. Among these changes, we find alterations in lipoprotein metabolism (high TG, high free fatty acids, low HDL) and in cholesterol homeostasis (low HDL, small dense LDL, “dysfunctional’ HDL), which are jointly known as the “atherogenic lipid profile.” All of these adaptations aim at the short-term redistribution of energy and modulation of the inflammatory reaction and the repair of the damage produced by the immune system, but in the long run will cause the metabolic syndrome and its associated diseases. Whether SFA plays a relevant contributing role in the development of chronic systemic low-grade inflammation (the central factor in this pathophysiological cascade) is dependent on many other factors that contribute to inflammation or its inhibition. Among the inflammatory factors are lack of exercise, high dietary ω6/ω3 ratio, chronic stress, anxiety and depression, air pollution (smoking included) and insufficient sleep. Anti-inflammatory factors are, e.g., physical exercise, fish and fish oil, high fruits, vegetables and fiber, low-GL foods, low psychosocial stress and adequate sleep [13].

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