Hepatoprotective effects of Spirulina maxima in patients with non-alcoholic fatty liver disease: a case series

<p>Abstract</p> <p>Introduction</p> <p>Non-alcoholic fatty liver diseases range from simple steatosis to non-alcoholic steatohepatitis. The "two hits" hypothesis is widely accepted for its pathogenesis: the first hit is an increased fat flux to the liver, which predisposes our patient to a second hit where increasing free fatty acid oxidation into the mitochondria leads to oxidative stress, lipoperoxidation and a chain reaction with increased ROS. Clinical indications include abdominal cramps, meteorism and fatigue. Most patients, however, are asymptomatic, and diagnosis is based on aminotransferase elevation and ultrasonography (or "brilliant liver"). Spirulina maxima has been experimentally proven to possess <it>in vivo </it>and <it>in vitro </it>hepatoprotective properties by maintaining the liver lipid profile. This case report evaluates the hepatoprotective effects of orally supplied Spirulina maxima.</p> <p>Case presentation</p> <p>Three Hispanic Mexican patients (a 43-year-old man, a 77-year-old man and a 44-year-old woman) underwent ultrasonography and were treated with 4.5 g/day of Spirulina maxima for three months. Their blood samples before and after the treatment determined triacylglycerols, total cholesterol, high-density lipoprotein cholesterol, alanine aminotransferase and low-density lipoprotein cholesterol levels. The results were assessed using ultrasound.</p> <p>Conclusion</p> <p>Treatment had therapeutic effects as evidenced by ultrasonography and the aminotransferase data. Hypolipidemic effects were also shown. We conclude that Spirulina maxima may be considered an alternative treatment for patients with non-alcoholic fatty liver diseases and dyslipidemic disorder.</p

Maternal Obesity during Gestation Impairs Fatty Acid Oxidation and Mitochondrial SIRT3 Expression in Rat Offspring at Weaning

In utero exposure to maternal obesity increases the offspring's risk of obesity in later life. We have also previously reported that offspring of obese rat dams develop hepatic steatosis, mild hyperinsulinemia, and a lipogenic gene signature in the liver at postnatal day (PND)21. In the current study, we examined systemic and hepatic adaptations in male Sprague-Dawley offspring from lean and obese dams at PND21. Indirect calorimetry revealed decreases in energy expenditure (p<0.001) and increases in RER values (p<0.001), which were further exacerbated by high fat diet (45% kcals from fat) consumption indicating an impaired ability to utilize fatty acids in offspring of obese dams as analyzed by PRCF. Mitochondrial function is known to be associated with fatty acid oxidation (FAO) in the liver. Several markers of hepatic mitochondrial function were reduced in offspring of obese dams. These included SIRT3 mRNA (p = 0.012) and mitochondrial protein content (p = 0.002), electron transport chain complexes (II, III, and ATPase), and fasting PGC-1α mRNA expression (p<0.001). Moreover, hepatic LCAD, a SIRT3 target, was not only reduced 2-fold (p<0.001) but was also hyperacetylated in offspring of obese dams (p<0.005) suggesting decreased hepatic FAO. In conclusion, exposure to maternal obesity contributes to early perturbations in whole body and liver energy metabolism. Mitochondrial dysfunction may be an underlying event that reduces hepatic fatty acid oxidation and precedes the development of detrimental obesity associated co-morbidities such as insulin resistance and NAFLD

Toxicogenomic Analysis Suggests Chemical-Induced Sexual Dimorphism in the Expression of Metabolic Genes in Zebrafish Liver

10.1371/journal.pone.0051971PLoS ONE712

Silencing hepatic MCJ attenuates non-alcoholic fatty liver disease (NAFLD) by increasing mitochondrial fatty acid oxidation

Nonalcoholic fatty liver disease (NAFLD) is considered the next major health epidemic with an estimated 25% worldwide prevalence. No drugs have yet been approved and NAFLD remains a major unmet need. Here, we identify MCJ (Methylation-Controlled J protein) as a target for non-alcoholic steatohepatitis (NASH), an advanced phase of NAFLD. MCJ is an endogenous negative regulator of the respiratory chain Complex I that acts to restrain mitochondrial respiration. We show that therapeutic targeting of MCJ in the liver with nanoparticle- and GalNAc-formulated siRNA efficiently reduces liver lipid accumulation and fibrosis in multiple NASH mouse models. Decreasing MCJ expression enhances the capacity of hepatocytes to mediate beta -oxidation of fatty acids and minimizes lipid accumulation, which results in reduced hepatocyte damage and fibrosis. Moreover, MCJ levels in the liver of NAFLD patients are elevated relative to healthy subjects. Thus, inhibition of MCJ emerges as an alternative approach to treat NAFLD. Non-alcoholic fatty liver (NAFLD) disease causes degeneration of the liver, affects about 25% of people globally, and has no approved treatment. Here, the authors show that the therapeutic siRNA-driven silencing of MCJ in the liver is an effective and safe treatment for NAFLD in multiple mouse models.We thank Douglas Taatjes and Nicole Bouffard for help with confocal microscopy analysis (Microscopy Imaging Center) at the University of Vermont. We also thank the University of Vermont Medical Center's Department of Pathology and Laboratory Medicine Histology and Clinical Laboratories for assistance with liver section staining and AST/ALT measurement, respectively. This work was supported by NIH STTR R41DK112429 (M.R.), NIH PO GM103496 (M.R.), Mitotherapeutix LLC (M.R., K.F, and M.L.M.-C.), MINECO/Feder SAF2015-65327-R and RTI2018-096494-B-100 (J.A.), MINECO/Feder SAF2017-87301-R (M.L.M-C.), BIOEF (M.L.M.-C.), EITB Maratoia BIO15/CA/014 (M.L.M-C), BBVA (M.L.M.-C.), La Caixa Foundation (M.L.M.-C.), Basque Country Health Department 2013111114 (M.L.M-C), MINECO/Feder SAF2015-64352-R (P.A.) and MINECO-Feder RTI2018-095134-B-100 (P.A.). ISCIII-Feder PI17/00535 (C.G.-M.), ISCIII-Feder CP14/00181, and PI16/00823 (A.G-R.), and Francisco Cobos Foundation (A.G.-R.). CIC bioGUNE is the recipient of a Severo Ochoa Excellence Accreditation (SEV-2016-0644) by the Ministry of Science, Innovation and Universities

A metabolomics cell-based approach for anticipating and investigating drug-induced liver injury

In preclinical stages of drug development, anticipating potential adverse drug effects such as toxicity is an important issue for both saving resources and preventing public health risks. Current in vitro cytotoxicity tests are restricted by their predictive potential and their ability to provide mechanistic information. This study aimed to develop a metabolomic mass spectrometry-based approach for the detection and classification of drug-induced hepatotoxicity. To this end, the metabolite profiles of human derived hepatic cells (i.e., HepG2) exposed to different well-known hepatotoxic compounds acting through different mechanisms (i.e., oxidative stress, steatosis, phospholipidosis, and controls) were compared by multivariate data analysis, thus allowing us to decipher both common and mechanism-specific altered biochemical pathways. Briefly, oxidative stress damage markers were found in the three mechanisms, mainly showing altered levels of metabolites associated with glutathione and γ-glutamyl cycle. Phospholipidosis was characterized by a decreased lysophospholipids to phospholipids ratio, suggestive of phospholipid degradation inhibition. Whereas, steatosis led to impaired fatty acids β-oxidation and a subsequent increase in triacylglycerides synthesis. The characteristic metabolomic profiles were used to develop a predictive model aimed not only to discriminate between non-toxic and hepatotoxic drugs, but also to propose potential drug toxicity mechanism(s)

Rôle des acides gras dans l’induction du cytochrome P450 2E1 hépatique : implication dans l’étiologie de la stéatohépatite non alcoolique et dans l’hépatotoxicité du paracétamol

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