Table 4.

Nutraceuticals with clinical effects on NAFLD: Main mechanisms of action, clinical effects, tested dosages, side effects, and level of clinical Evidence.

Nutraceutical	Tested Dosages	Proposed Mechanism of Actions	Clinical Effects	Side Effects	Level of Scientific Evidence [Ref.]
Berberine	500–500 mg/day	Activation of AMPK and the expression of LDL receptors, inhibition of PCSK9	Improvement of levels of indirect markers of hepatosteatosis (Hepatic Steatosis Index, Lipid Accumulation Product), lipid parameters and insulin resistance	Mild gastrointestinal side effects	Meta-analysis of RCTs [69,84]
Coenzyme Q10	100–300 mg/day	Antioxidant activity, sensitizing of Ca++ channels, inductor of the synthesis of ATP, reduction of oxidative stress and lipid peroxidation	Reduction of transaminases, gamma-GT, hsCRP and degrees of NAFLD and hepatic steatosis, improvement of the adiponectin/leptin ratio	Not reported	RCTs [64,65,68]
Curcumin	400–2000 mg/day	Inhibition of the expression of NPC1L1 transporter, increases the efflux of cholesterol, downregulation of the expression of PCSK9, reduction of TNF-α levels, inhibition of NF-κB activation, lipid peroxidation and lysosomal enzyme activities, induction of PPAR-γ and Nrf2 activation	Improvement in the degree of hepatic steatosis, reduction in transaminase levels, waist circumference and body mass index	Mild nausea, stomach cramps and/or upset, diarrhea, dizziness	Meta-analysis of RCTs [71,72]
Polyunsaturated Omega-3 fatty acids	1–4 g/day of eicosapentanoic and/or docosahexaenoic acid	Reduction of the release and synthesis of inflammatory cytokines, activation of eNOS, prostaglandins synthesis balance toward vasodilating ones, insulin-sensitivity, vascular tone regulation by parasympathetic nervous system stimulation, and suppression of the renin–angiotensin–aldosterone system	Reduction of transaminases, serum triglycerides, blood pressure (SBP 1–5 mmHg)	Mild aftertaste, nausea, gastroesophageal reflux, bloating and dyspepsia	Meta-analysis of RCTs [58,59]
Probiotics	>3,5 CFU/day (extremely variable depending on strains, associations, and vehicle of administration used)	Reduction of lucky gut syndrome, intestinal permeability, modulation of bile salt hydrolases	Improvement of insulin resistance, plasma levels of transaminases, degree of lipid infiltration of the liver	Not reported	RCTs [78]
Resveratrol	>150 mg/day	Antioxidant, vasoprotective (both cerebral and peripheral) and insulin-sensitizing activity	Unclear	Rare gastrointestinal side effects	Open-label clinical studies [75,76]
Silymarin	150–450 mg/day	Direct scavenger activity, mitochondrial function optimization, activation of protective molecules such as HSPs, thioredoxin and sirtuins, inhibition of NF-kB activity, proinflammatory cytokine synthesis reduction (IL-1, IL-6, TNF-α), modulation of caspase release and TNF-α effect, inhibition of the conversion of stellate cells into fibroblasts, downregulation of the expression of profibrotic genes (procollagen III, TGF-β), partial activation of estrogen receptors, insulin-sensitizing action, PPAR-agonist action, increased expression of GLUT4 on the cell surface, inhibition of HMG-CoA reductase, upregulation of the bile salt export pump	Transaminase normalization, reduction of gamma-glutamyl transferase levels and degree of ultrasound-related liver steatosis, improvement of fasting glucose, basal insulinemia and insulin resistance	Mild gastrointestinal side effects	Meta-analysis of RCTs [29,30,31]
Vitamin D	2000–50,000 UI/day	Upregulation of the translocation of GLUT4, modulation of transcription of insulin gene, inhibition of NF-kB, release of proinflammatory cytokines and proliferation of hepatic stellate cells	Improvement of insulin sensitivity, hepatic and adipose inflammation	Not reported	RCTs [54,55]
Vitamin E	800 UI/day	Antioxidant	Improvement of arterial stiffness and reduction of risk of myocardial infarction	At 400 UI/day: increases risk of mortality (?)	Meta-analysis of RCTs [33,34,35]

AMPK = Adenosin-Monophosphate-Kinase-alpha, CFU = colony forming units, eNOS = endothelial nitric oxide synthase, GLUT4 = glucose transporter type 4, HMG-CoA = Hydroxy-Methyl-Glutaryl Coenzyme A, hs-CRP = high sensible C-reactive protein, IL = Interleukin, NF-κB = nuclear factor kappa-light-chain-enhancer of activated B cells, NPC1L1 = Niemann-Pick C1-Like 1) Nrf2 = nuclear factor erythroid-2-related factor-2, PCSK9 = proprotein convertase subtilisin/kexin type 9, PPAR = peroxisome proliferator-activated receptor, TGF-β = transforming growth factor beta, TNF = tumor necrosis factor, RCTs = Randomized clinical trials.