How Does CBG Administration Affect Sphingolipid Deposition in the Liver of Insulin-Resistant Rats?

BACKGROUND: Cannabigerol (CBG), a non-psychotropic phytocannabinoid found in Cannabis sativa plants, has been the focus of recent studies due to its potential therapeutic properties. We proposed that by focusing on sphingolipid metabolism, which plays a critical role in insulin signaling and the development of insulin resistance, CBG may provide a novel therapeutic approach for metabolic disorders, particularly insulin resistance. METHODS: In a rat model of insulin resistance induced by a high-fat, high-sucrose diet (HFHS), we aimed to elucidate the effect of intragastrically administered CBG on hepatic sphingolipid deposition and metabolism. Moreover, we also elucidated the expression of sphingolipid transporters and changes in the sphingolipid concentration in the plasma. RESULTS: The results, surprisingly, showed a lack of changes in de novo ceramide synthesis pathway enzymes and significant enhancement in the expression of enzymes involved in ceramide catabolism, which was confirmed by changes in hepatic sphingomyelin, sphinganine, sphingosine-1-phosphate, and sphinganine-1-phosphate concentrations. CONCLUSIONS: The results suggest that CBG treatment may modulate sphingolipid metabolism in the liver and plasma, potentially protecting the liver against the development of metabolic disorders such as insulin resistance.

Coumestrol as a new substance that may diminish lipid precursors of the inflammation in steatotic primary rat hepatocytes.

Coumestrol is a phytoestrogen found in various plant foods. Increasing evidence ascertained its robust anti-inflammatory, anti-oxidative properties likewise ability to mitigate insulin resistance. Thus, it may be a potential medicine in the treatment of many metabolic disorders, including obesity, type 2 diabetes (T2D) as well as non-alcoholic fatty liver disease (NAFLD). In this study, we aimed to shed some light on its influence on the accumulation of certain lipid fractions and the expression of pro-inflammatory proteins in primary rat hepatocytes during the lipid-overload state. The cells were isolated from the male Wistar rat's liver with the use of collagenase perfusion. It was followed by incubation of the cells with the presence or absence of palmitic acid and/or coumestrol. The accumulation of lipid fractions was assessed by gas-liquid chromatography (GLC) whereas the expression of the proteins was evaluated by the Western blot technique. Treatment with coumestrol in the state of increased fatty acids availability led to the deposition of triacylglycerols rather than diacylglycerols, significantly decreased expression of proinflammatory and profibrotic cytokines, especially interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α), as well as transforming growth factor ß (TGF-ß), and nuclear factor κß (NF-κß). Also, we observed a substantial diminution in proinflammatory enzymes expression. Taking into consideration the direction of the aforementioned changes, we may assume that coumestrol can ameliorate the array of factors leading to the development of steatosis, likewise counteracting progression to steatohepatitis, thus it may be a step forward to the long-awaited breakthrough in the treatment of NAFLD.

Influence of vitamin K2 on lipid precursors of inflammation and fatty acids pathway activities in HepG2 cells.

Vitamin K2 (VK2) is one of the two types of vitamin K present most in the human diet. VK2 seems to have a beneficial effect on inflammation related to type 2 diabetes mellitus. The aim of this study was to evaluate the influence of VK2 on lipid precursors of inflammation in lipid-overloaded human liver hepatocellular carcinoma cells. Cells were incubated with VK2 and/or palmitic acid (PA). The concentrations of lipid fractions and their fatty acid compositions were measured by gas-liquid chromatography. The expression of proteins involved in the inflammatory process was detected using western blotting. The concentration of triacylglycerols (TAGs), activities of the n-3 pathway in TAGs, and lipooxygenase 15 expression were significantly elevated in cells incubated with PA and VK2. In the same group, a marked elevation in diacylglycerol (DAG) 20:4 was observed. VK2 supplementation lowered the expression of tumour necrosis factor-alpha and interleukin-6 compared to that in the PA group. The data indicate that VK2 redirects fatty acid metabolism into the deposition of a safe TAG fraction by increasing the concentration of anti-inflammatory n-3 polyunsaturated fatty acids in this fraction. Moreover, VK2 stimulates the synthesis of anti-inflammatory factors and has anti-inflammatory effects by reducing DAG 20:4.