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.
Highlights
Non-alcoholic fatty liver disease (NAFLD) or fatty liver is the benign evidence of the metabolic syndrome, which affects 25% of the obese adult population worldwide
Indirect calorimetry in wild type (WT) and HET mice placed on a high fat diet (HFD) drinking or not drinking melatonin was performed at the beginning of treatments, after 7 or 15 weeks of dietary intake
This interesting trend was evident during the hours of dark, when melatonin compensated for the HFD induced loss in locomotor activity largely in WT rather than HET mice (Figure S1F)
Summary
Non-alcoholic fatty liver disease (NAFLD) or fatty liver is the benign evidence of the metabolic syndrome, which affects 25% of the obese adult population worldwide. NAFLD evolves into steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC) [1,2,3,4]. Cells 2019, 8, 1053 not a peculiar therapy able to block the onset, progression and staging of the disease and preclinical experimental rodent NAFLD models are indispensable to discover novel therapeutic targets [5,6]. NAFLD is defined a “mitochondrial disease”, because damaged mitochondria and sustained production of reactive oxygen species have been detected in the liver of obese and diabetic patients [12,13]. The adverse progression from fatty liver to severe NASH and HCC is characterized by persistent mitochondrial damage [14]
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