Melatonin Effects on Non-Alcoholic Fatty Liver Disease Are Related to MicroRNA-34a-5p/Sirt1 Axis and Autophagy

Abstract

Melatonin, an indole produced by pineal and extrapineal tissues, but also taken with a vegetarian diet, has strong anti-oxidant, anti-inflammatory and anti-obesogenic potentials. Non-alcoholic fatty liver disease (NAFLD) is the hepatic side of the metabolic syndrome. NAFLD is a still reversible phase but may evolve into steatohepatitis (NASH), cirrhosis and carcinoma. Currently, an effective therapy for blocking NAFLD staging is lacking. Silent information regulator 1 (SIRT1), a NAD+ dependent histone deacetylase, modulates the energetic metabolism in the liver. Micro-RNA-34a-5p, a direct inhibitor of SIRT1, is an emerging indicator of NAFLD grading. Thus, here we analyzed the effects of oral melatonin against NAFLD and underlying molecular mechanisms, focusing on steatosis, ER stress, mitochondrial shape and autophagy. Male C57BL/6J (WT) and SIRT1 heterozygous (HET) mice were placed either on a high-fat diet (58.4% energy from lard) (HFD) or on a standard maintenance diet (8.4% energy from lipids) for 16 weeks, drinking melatonin (10 mg/kg) or not. Indirect calorimetry, glucose tolerance, steatosis, inflammation, ER stress, mitochondrial changes, autophagy and microRNA-34a-5p expression were estimated. Melatonin improved hepatic metabolism and steatosis, influenced ER stress and mitochondrial shape, and promoted autophagy in WT HFD mice. Conversely, melatonin was ineffective in HET HFD mice, maintaining NASH changes. Indeed, autophagy was inconsistent in HET HFD or starved mice, as indicated by LC3II/LC3I ratio, p62/SQSTM1 and autophagosomes estimation. The beneficial role of melatonin in dietary induced NAFLD/NASH in mice was related to reduced expression of microRNA-34a-5p and sterol regulatory element-binding protein (SREBP1) but only in the presence of full SIRT1 availability.

Self-eating: friend or foe? The emerging role of autophagy in fibrotic diseases

“…Silent information regulator 1 (SIRT1), an NAD + dependent histone deacetylase, regulated energy and lipid homeostasis in the liver, and miR-34a-5p was the direct inhibitor of SIRT1. Melatonin reversed HFD-caused liver fibrosis and NAFLD by increasing the ratio of LC3-II/I, decreasing cytoplasmic p62 levels and reducing the expression of miR-34a-5p in WT, but not SIRT1 heterozygous (HET) mice 64 . Similar to previous results, the activation of autophagy by rapamycin alleviated methionine choline-deficient (MCD) diet-caused liver fibrosis in a NASH mouse model 65 .…”

The Interplay between Oxidative Stress and miRNAs in Obesity-Associated Hepatic and Vascular Complications

“…Pterostilbene, a resveratrol analogue found in edible berries, downregulates miR-34a overexpression in fructose fed rats, leading to the restoration of SIRT1 activity and the inhibition of SREBP-1 lipogenic activity [ 100 ]. Melatonin is naturally found in edible plants and may be responsible for lower expression of miR-34a in melatonin-treated HFD-fed mice, along with higher SIRT1 and lower SREBP-1 activities [ 101 ]. Finally, the novel carnosic acid decreases miR-34a overexpression, alleviates dyslipidemia and activates the anti-apoptotic properties of SIRT1 in rats submitted to a HFD [ 102 ].…”

<p>Galangin Improved Non-Alcoholic Fatty Liver Disease in Mice by Promoting Autophagy</p>

“…8 Accumulating evidence suggests important links between the regulation of autophagy and liver complications associated with obesity and NAFLD. [9][10][11] In particular, a previous study of the drug liraglutide indicated that the promotion of autophagy can ameliorate the effects of NAFLD via the SIRT1/SIRT3-FOXO3a pathway. 10 The autophagy process is dependent on a multitude of signaling pathways.…”