Exploring the impacts of ketogenic diet on reversible hepatic steatosis: initial analysis in male mice.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common chronic liver disease. Ketogenic diet (KD), a diet with very low intake in carbohydrates, gained popularity as a weight-loss approach. However, in mice models, it has been reported that an excess exposition of dietary fat induces hepatic insulin resistance and steatosis. However, data published is inconsistent. Herein, we investigated in a mouse model, the metabolic effects of KD and its contribution to the pathogenesis of NALFD. Mice were exposed to KD or CHOW diet for 12 weeks while a third group was exposed to KD for also 12 weeks and then switched to CHOW diet for 4 weeks to determine if we can rescue the phenotype. We evaluated the effects of diet treatments on fat distribution, glucose, and insulin homeostasis as well as hepatic steatosis. Mice fed with KD developed glucose intolerance but not insulin resistance accompanied by an increase of inflammation. KD-fed mice showed an increase of fat accumulation in white adipose tissue and liver. This effect could be explained by an increase in fat uptake by the liver with no changes of catabolism leading to MAFLD. Interestingly, we were able to rescue the phenotype by switching KD-fed mice for 4 weeks on a CHOW diet. Our studies demonstrate that even if mice develop hepatic steatosis and glucose intolerance after 12 weeks of KD, they do not develop insulin resistance and more importantly, the phenotype can be reversed by switching the mice from a KD to a CHOW.

Cerebral Apolipoprotein D Exits the Brain and Accumulates in Peripheral Tissues.

Apolipoprotein D (ApoD) is a secreted lipocalin associated with neuroprotection and lipid metabolism. In rodent, the bulk of its expression occurs in the central nervous system. Despite this, ApoD has profound effects in peripheral tissues, indicating that neural ApoD may reach peripheral organs. We endeavor to determine if cerebral ApoD can reach the circulation and accumulate in peripheral tissues. Three hours was necessary for over 40% of all the radiolabeled human ApoD (hApoD), injected bilaterally, to exit the central nervous system (CNS). Once in circulation, hApoD accumulates mostly in the kidneys/urine, liver, and muscles. Accumulation specificity of hApoD in these tissues was strongly correlated with the expression of lowly glycosylated basigin (BSG, CD147). hApoD was observed to pass through bEnd.3 blood brain barrier endothelial cells monolayers. However, cyclophilin A did not impact hApoD internalization rates in bEnd.3, indicating that ApoD exit from the brain is either independent of BSG or relies on additional cell types. Overall, our data showed that ApoD can quickly and efficiently exit the CNS and reach the liver and kidneys/urine, organs linked to the recycling and excretion of lipids and toxins. This indicated that cerebral overexpression during neurodegenerative episodes may serve to evacuate neurotoxic ApoD ligands from the CNS.

Monounsaturated Fatty Acids in Obesity-Related Inflammation.

Obesity is an important aspect of the metabolic syndrome and is often associated with chronic inflammation. In this context, inflammation of organs participating in energy homeostasis (such as liver, adipose tissue, muscle and pancreas) leads to the recruitment and activation of macrophages, which secrete pro-inflammatory cytokines. Interleukin-1ß secretion, sustained C-reactive protein plasma levels and activation of the NLRP3 inflammasome characterize this inflammation. The Stearoyl-CoA desaturase-1 (SCD1) enzyme is a central regulator of lipid metabolism and fat storage. This enzyme catalyzes the generation of monounsaturated fatty acids (MUFAs)-major components of triglycerides stored in lipid droplets-from saturated fatty acid (SFA) substrates. In this review, we describe the molecular effects of specific classes of fatty acids (saturated and unsaturated) to better understand the impact of different diets (Western versus Mediterranean) on inflammation in a metabolic context. Given the beneficial effects of a MUFA-rich Mediterranean diet, we also present the most recent data on the role of SCD1 activity in the modulation of SFA-induced chronic inflammation.

Hexanoic, Octanoic and Decanoic Acids Promote Basal and Insulin-Induced Phosphorylation of the Akt-mTOR Axis and a Balanced Lipid Metabolism in the HepG2 Hepatoma Cell Line.

Metabolic illnesses such as non-alcoholic fatty liver disease (NAFLD) are in constant increase worldwide. Highly consumed long chain fatty acids (LCFA) are among the most obesogenic and steatogenic nutrients. Hepatic steatosis is associated with several complications such as insulin resistance. Growing evidence points to medium chain fatty acids (MCFA), more efficiently oxidized than LCFA, as a promising dietary alternative against NAFLD. However, reports on the hepatic effects of MCFA are sometimes conflicting. In this study we exposed HepG2 cells, a human hepatocellular model, to 0.25 mM of hexanoic (C6), or octanoic (C8), and decanoic (C10) acids separately or in a C8 + C10 equimolar mix reflecting commercially available MCFA-rich oils. We found that C6, a poorly studied MCFA, as well as C8 and C10 did not provoke the deleterious lipid anabolism runaway typically induced by LCFA palmitate. MCFA tended, instead, to promote a balanced metabolic profile and were generally non-cytotoxic. Accordingly, mitochondrial integrity was mostly preserved following MCFA treatment. However, treatments with C8 induced a mitochondrial membrane potential decrease, suggesting prolonged exposure to this lipid could be problematic. Finally, MCFA treatments maintained optimal insulin sensitivity and even fostered basal and insulin-dependent phosphorylation of the Akt-mTOR pathway. Overall, MCFA could constitute an effective nutritional tool to manage liver steatosis and hepatic insulin resistance.

L-carnitine protects C2C12 cells against mitochondrial superoxide overproduction and cell death.

AIM: To identify and characterize the protective effect that L-carnitine exerted against an oxidative stress in C2C12 cells. METHODS: Myoblastic C2C12 cells were treated with menadione, a vitamin K analog that engenders oxidative stress, and the protective effect of L-carnitine (a nutrient involved in fatty acid metabolism and the control of the oxidative process), was assessed by monitoring various parameters related to the oxidative stress, autophagy and cell death. RESULTS: Associated with its physiological function, a muscle cell metabolism is highly dependent on oxygen and may produce reactive oxygen species (ROS), especially under pathological conditions. High levels of ROS are known to induce injuries in cell structure as they interact at many levels in cell function. In C2C12 cells, a treatment with menadione induced a loss of transmembrane mitochondrial potential, an increase in mitochondrial production of ROS; it also induces autophagy and was able to provoke cell death. Pre-treatment of the cells with L-carnitine reduced ROS production, diminished autophagy and protected C2C12 cells against menadione-induced deleterious effects. CONCLUSION: In conclusion, L-carnitine limits the oxidative stress in these cells and prevents cell death.