Roberto Carlos Burini*, Hugo Tadashi Kano, Layene Peixoto Barros, Núbia Alves Grandini and Camila Renata Corrêa
Mammals have evolved mechanisms to store energy during periods of plenty, which helps to guarantee survival during periods of drought and famine. The fatthriftiness accomplishes our ability to effectively detect, metabolize, and store fats. For so, variable amounts of extra fat are safely stored subcutaneously, either locally hip and thigh (in adults) or spread over total body subcutaneous (in children), where it confers a metabolically protective reserve in both genders and supports pregnancy and lactation in females. For so, dedicated fat-storing cells were necessary, because the tissues of the lean body mass lack the storage capacity to meet the fuel demands. Consequently, hypertrophy and hyperplasia of adipocytes can occur in energy surplus, with adipocyte hypertrophy controlling both, the differentiation of neo-adipocytes(increasing fat storage) and the local macrophage density for fat surplus scavenging. Therefore, macrophage-scavenger (pro-inflammatory) actions are part of the cell defense against fat-overstored (hypertrophied) adipocytes. The fat balance in non-adipocyte cell is maintained between uptake (and produced) and oxidation of fatty acids. The process has hormonal control of insulin and adipokines, leptin and adiponectin. The excess of fat is primarily stored in the form of neutral fat, as triglycerides, which are the least toxic form of neutral fat to be stored, whereas its alternative, de novo ceramide formation, is probably the most damaging lipid. Increased ceramide synthesis leads to both leptin and insulin resistance. Insulin resistance may be one example of cell-lipotoxicity by lipid accumulation in skeletal muscle(myoesteatosis) and liver(esteatosis). Insulin resistance can be consequent to factors such as inflammation, oxidative stress or Free-Fatty Acids (FFAs) accumulation in hepatocytes. The initial step of Non-Alcoholic Fatty Liver Disease (NAFLD) involves fat accumulation in the liver as a result of the excessive delivery of FFAs from the adipose tissue(lipolysis) and an imbalance between lipid synthesis and export in hepatocyte. NAFLD is the most common cause of chronic liver disease, constituting a major risk factor for progression to liver failure, cirrhosis, and also, hepatocellular carcinoma. Approximately 10–30% NAFLD have the potentially progressive form of Non-Alcoholic Steato-Hepatitis (NASH) and, approximately 25–40% of patients with NASH will develop progressive liver fibrosis, which is associated with hepatocellular injury and inflammation, with a poor long-term prognosis. Our sample showed 59.6% NAFLD and 0.6% liver fibrosis with the latter increased 6X by the presence of NAFLD. The NAFLD progression to NASH occurs through the first hit of hepatocytes by saturated fatty acids coming from peripheral lipolysis, complemented by a second inflammatory hit consequent to gut dysbiosis. In our data plasma Lipopolysaccharide-Binding Protein (LBP) correlates significantly with Fatty-Liver Index(r= 0.90). Additionally, our data showed that inflammation and insulin resistance had similar impact on the prevalence of NAFLD and hepatic fibrosis, both far below the oxidative stress impact. The expected consequences of inflammation and oxidative stress are insulin resistance with fasting hyperglycemia and atherogenic dyslipidemia pointing out toward cardiovascular mortality as the leading cause of death in patients with NAFLD. For though, it is suggested that liver esteatosis predates clinical CVDs, and may trigger or accelerate its occurrence. In our data, the atherosclerotic course of NAFLD to Coronary-Heart Disease (CHD) was accentuated by the presence of T2D. Our proposed mechanism for this NAFLD-CHD interplay is based on the underlying background of gluco-lipotoxicity(of T2D) involving inflammation(of NAFLD) and oxidative stress(of T2D) leading to insulin resistance. Besides highly related with metabolic stress markers of gluco-lipotoxicity, NAFLD and related CVDs showed a wide pattern of liver-born proteins, some positively related to acute-phase inflammation (LBP, CRProtein and Fetuin-A) and, other negatively related such as albumin. Similarly, some peptide of antioxidant defense such as GSH was reduced by the presence of NAFLD and gluco-lipotoxicity, in opposition of increased oxidized products GSSG and MDA. From those markers, Fetuin-A presented a potential diagnostic power as a biomarker for grading insulin resistance and cardiovascular diseases, both related to liver dysfunction. Moreover, we showed that plasma Fetuin-A level responded positively to Lifestyle-change protocols.
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