Induction ofin vitroketosis condition and suppression using methylsulfonylmethane by altering ANGPTL3 expression through STAT5b signaling mechanism

Abstract

Ketosis is a condition where ketone bodies are used as the energy source instead of glucose. The state of ketosis becomes dangerous if the fat metabolism in the body is high. When the glucose availability gets limited, liver activates fat metabolism to make glucose for energy. As the results of these, ketone bodies will form resulting the state of ketosis. In the present study, we analyzed the in vitro ketosis condition and the effect of glucose level in ketosis induction. The natural organic sulfur containing compound methylsulfonylmethane (MSM) was analyzed for anti-ketosis activity in normal mouse hepatocyte, FL83B cell model system. Ketosis condition was induced by modulating glucose concentration. Growth hormone receptor (GHR) has a great role in the ketosis condition. We hypothesize that MSM has the ability to regulate GHR signaling through signal transducer and activator of transcription 5b (STAT5b). The whole cell lysate analysis and DNA binding activity analysis also suggested the critical role of STAT5b in ketosis condition. Angiopoietin-like 3 (ANGPTL3) protein is a molecular target to treat ketosis. STAT5b is a transcription factor for ANGPTL3. We elucidated the treatment of ketosis through the control of molecular targets such as ANGPTL3, STAT5b, and GHR by MSM, and we also evaluated the relation between ANGPTL3 and STAT5b signaling molecules as critical regulators. IntroductionMost of the energy in the body is provided by blood glucose by means of glycolysis. However, when liver glucogen stores are depleted, the system tends to switch on the fat metabolism. As a result, ketone bodies are formed by ketogenesis. Thereafter, most of the body's energy comes from ketone bodies in a metabolic state known as ketosis. If the body is said to be in ketosis condition, then the concentration of ketone bodies in serum is over 0.5 mM with low and consistent blood glucose level. In hyperketonemia condition, there is an increased level of ketone bodies. The ketone bodies that take part in the energy formation are acetate, acetoacetate, and β-hydroxybutyrate (BHB; Laffel 1999) where insulin and glucagon regulate their level (Johnston et al. 1982). The state of ketosis is more related with carbohydrate and fat metabolism. When the body is in fasting or running with low glucose, the metabolism shifts to ketosis until the body gets a carbohydrate-rich meal to change the metabolism to glycolysis. Ketosis is considered to be in a fat-burning mode because fat reserves are readily released and consumed in ketosis.

Methylsulfonylmethane Induces G1 Arrest and Mitochondrial Apoptosis in YD-38 Gingival Cancer Cells

“…Our recent study proved that MSM is able to up-regulate the expression levels of growth hormone receptor (GHR) and signal transducer and activator of transcription 5b (STAT5b) in osteoblast-like cells (16). It is also able to inhibit in vitro ketosis in mouse hepatocytes (17).…”

Silibinin inhibits in vitro ketosis by regulating HMGCS2 and NF-kB: elucidation of signaling molecule relationship under ketotic conditions

“…The induction of in vitro ketosis with the glucose starvation method can be used to identify anti-ketosis effects of a candidate drug (Sreekantan Preetha et al 2015). Here, we used the low glucose concentration (0.12%) media (F-12K) to induce ketosis, and we increased the glucose concentration thrice for control conditions (high-glucose condition; 3.78 g/l; 0.37% glucose).…”

“…The glucose levels in the body are significantly different in normal conditions and ketotic conditions; low-glucose conditions induce the body to use fat as an alternative energy source; hence, ketosis ensues. Thus, the induction of in vitro ketotic conditions is not difficult; it can be achieved by varying the amount of glucose (D-glucose) in the cell culture medium (Sreekantan Preetha et al 2015).…”

Sulfur Compounds Inhibit High Glucose-Induced Inflammation by Regulating NF-κB Signaling in Human Monocytes

“…Methylsulfonylmethane (MSM) is also a natural organic sulfur-containing compound present in food and beverages [33]. MSM has various properties, such as anticancer [34], antioxidant [35], and anti-ketotic [36] activities, which make it a promising drug candidate. MSM also has the ability to inhibit inflammatory responses in relation to TNF-α in cardiac cells [37].…”