Increasing Dietary Medium-Chain Fatty Acid Ratio Mitigates High-fat Diet-Induced Non-Alcoholic Steatohepatitis by Regulating Autophagy

Abstract

Previous studies have demonstrated that saturated fatty acids (SFAs) are more lipotoxic than unsaturated fatty acids (UFAs) in inhibiting hepatic autophagy and promoting non-alcoholic steatohepatitis (NASH). However, there have been few studies have investigated the effects of carbon chain length on SFA-induced autophagy impairment and lipotoxicity. To investigate whether SFAs with shorter carbon chain lengths have differential effects on hepatic autophagy and NASH development, we partially replaced lard with coconut oil to elevate the ratio of medium-chain fatty acids (MCFAs) to long-chain fatty acids (LCFAs) in a mouse high-fat diet (HFD) and fed mice for 16 weeks. In addition, we treated HepG2 cells with different combinations of fatty acids to study the mechanisms of MCFAs-mediated hepatic protections. Our results showed that increasing dietary MCFA/LCFA ratio mitigated HFD-induced Type 2 diabetes and NASH in mice. Importantly, we demonstrated that increased MCFA ratio exerted its protective effects by restoring Rubicon-suppressed autophagy. Our study suggests that the relative amount of LCFAs and MCFAs in the diet, in addition to the amount of SFAs, can significantly contribute to autophagy impairment and hepatic lipotoxicity. Collectively, we propose that increasing dietary MCFAs could be an alternative therapeutic and prevention strategy for Type 2 diabetes and NASH.

Modifying macronutrients is superior to microbiome transplantation in treating nonalcoholic fatty liver disease

“…Though the role of medium chain fatty acid (MCFA) and medium chain triglycerides (MCT) seems controversial as MCT has been shown to cause steatosis, 36 while other studies have shown they reduce steatosis and hepatic injury by upregulating fatty acid liver oxidation. 37,38 Although MCFAs are associated with decreasing the ratio of Firmicutes to Bacteroidetes leading to a reduction in steatosis, we did not observe such changes in the HFF mice. In contrast, the LFF diet had over 4 times less fat than both the NAFLD-inducing and the HFF diets and the fat present was mainly enriched in omega-3 PUFAs.…”

Chain length of saturated fatty acids regulates mitochondrial trafficking and function in sensory neurons

“…Modeling dyslipidemia in cultures of sensory DRG neurons also induces significant neuronal damage, including oxidative stress, impaired mitochondrial trafficking, dysfunctional axonal mitochondria, bioenergetic reprogramming, and neuronal dysfunction as a result of increased levels of LCSFAs (14-17, 27, 59, 60). In parallel, several recent studies also indicate that normalization of MCSFA levels in lard-based high-fat-diet mouse models leads to a reduction in adiposity and insulin resistance associated with T2D (24,25,56,(61)(62)(63), suggesting that cellular dysfunction is dependent on hydrocarbon chain length. These data support the rationale for our current evaluation of the impact of SFA hydrocarbon chain length on mitochondrial transport and function in the primary sensory DRG neurons damaged in DPN.…”

“…Moreover, the Western diet, characterized by increased intake of foods with high levels of long-chain SFAs (LCSFAs), including myristate (C14:0), palmitate (C16:0), and stearate (C18:0), and low levels of beneficial medium-chain SFAs (MCSFAs), such as laurate (C12:0) (20-22), is a driving factor in the onset of dyslipidemia and T2D (23). MCSFAs are reported to prevent lipotoxicity and increase mitochondrial energy production (18,24,25). Likewise, equimolar caloric intake of MCSFAs and LCSFAs increases mitochondrial energy expenditure and leads to oxidative metabolic pathways as opposed to the metabolic dysfunction triggered by LCSFAs (24,26).…”

The Selective Peroxisome Proliferator‐Activated Receptor Gamma Modulator CHS‐131 Improves Liver Histopathology and Metabolism in a Mouse Model of Obesity and Nonalcoholic Steatohepatitis

“…Shorter fatty acid chains have lower melting points, can be easily metabolized, and have been associated with reduced autophagy, improved liver status, and lower insulin resistance. (18,19) This finding may be the result of changes in fatty acid synthesis, elongation, or oxidation with CHS-131 treatment. (20) In the liver, we observed an up-regulation of Fabp4 and Fasn with CHS-131 treatment, indicating increased fatty acid uptake and synthesis, and no changes in genes related to mitochondrial function and fatty acid oxidation.…”