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Machado. Hepatoma Res 2020;6:84 I http://dx.doi.org/10.20517/2394-5079.2020.90 Page 7 of 18

cytokines such as TNF-a and interleukin-6 that stimulate proteolysis/muscle catabolism further
[91]
contributing to sarcopenia .

On the other hand, myosteatosis induces IR through FFA modulation of p38 mitogen-activated protein
[92]
kinase . The muscle is the primary organ responsible for insulin-mediated glucose disposal, hence a
[93]
decrease in muscle mass translates in impaired glucose metabolism, with postprandial hyperglycemia .
Sarcopenia also decreases the tolerance to exercise, further decreasing energy expenditure, exacerbating
[94]
energy surplus, and promoting weight gain and IR .

Myokines also have an important role in the pathogenesis of NAFLD. Irisin is an exercise-inducible
myokine that promotes transdifferentiation of white into brown adipose tissue, with upregulation of
[95]
uncoupling proteins, resulting in an increase in heat production, energy expenditure, and weight loss .
In the liver, irisin has direct anti-steatogenic effects through activation of PPAR-a and upregulation of
[88]
fibroblast growth factor (FGF)-21 . Accordingly, a study in obese patients showed a negative correlation
[96]
between irisin and hepatic steatosis severity . Myostatin is a myokine whose expression is downregulated
by exercise . Myosin has a negative impact on sarcopenia, since it promotes proteolysis and inhibits
[97]
[98]
muscle regeneration and function . Myostatin also has metabolic actions, promoting adipose tissue
expansion through direct effects on the adipose tissue and indirectly through downregulation of irisin [99,100] .
[101]
Lastly, myostatin has fibrogenic properties through direct action on hepatic stellate cells . Interestingly,
myostatin levels correlate with liver steatosis in lean subjects . Increased myostatin levels are also seen in
[69]
end-stage liver disease [102] , and associate with mortality in patients with liver cirrhosis [103] .

Sarcopenia and expansion of VAT act synergistically in the pathogenesis and progression of NAFLD. In
patients with NAFLD, a decrease in muscle mass and increase in VAT are associated with worsening of
steatosis and, more importantly, progression of liver fibrosis [104] .

Genetics
In 2008, a genome wide association study unraveled a polymorphism in patatin-like phospholipase domain-
containing protein 3 (PNPLA3), rs738409 C>G, encoding the substitution of isoleucine for methionine at
position 148 (I148M), which associates with increased risk for hepatic steatosis disconnected from obesity
or the MS [105,106] . Subsequent studies found that polymorphism is also associated with steatohepatitis,
advanced fibrosis. and progression to hepatocellular carcinoma [107-110] .

PNPLA3 (adiponutrin) is a membrane-bound protein highly expressed in the liver and adipose tissue,
that regulates remodeling of lipid droplets on hepatocytes and hepatic stellate cells. Diet can modulate
PNPLA3 expression. Carbohydrates upregulate [111,112] , whereas unsaturated fatty acids suppress PNPLA3
expression [113] . The rs738409 variant results in the accumulation of a dysfunctional adiponutrin on lipid
droplets [114] .

Regarding the role of PNPLA3 rs738409 on lean-NAFLD, studies consistently found an increased G allele
[28]
frequency on lean-NAFLD patients as compared to lean healthy subjects, mirroring studies on MAFLD .
Some studies also found an increased G allele or GG phenotype in lean vs. obese NAFLD patients [22,35,115,116] ,
though not all studies reproduced those findings [28,34,86,117] . An Italian study, albeit did not find a difference
between G allele frequencies in lean or obese NAFLD, found that this variant is associated with disease
severity (presence of steatohepatitis and significant fibrosis) only in lean patients [118] . Two meta-analyses
failed to find a difference in G allele between lean and obese patients with NAFLD [12,18] , which indicates
that variants in PNPLA3 might not be a major factor in the development of lean-NAFLD. Of note, Asian
studies showed higher differences in the PNPLA3 variant in lean-NAFLD as opposed to overweight/obese
NAFLD [119] , suggesting interplay between racial background and PNPLA3 phenotype in the development of
lean-NAFLD.