Abstract
IntroductionNonalcoholic fatty liver disease (NAFLD) can be seen as a manifestation of overnutrition. The muscle is a central player in the adaptation to energy overload, and there is an association between fatty-muscle and -liver. We aimed to correlate muscle morphology, mitochondrial function and insulin signaling with NAFLD severity in morbid obese patients.MethodsLiver and deltoid muscle biopsies were collected during bariatric surgery in NAFLD patients. NAFLD Activity Score and Younossi's classification for nonalcoholic steatohepatitis (NASH) were applied to liver histology. Muscle evaluation included morphology studies, respiratory chain complex I to IV enzyme assays, and analysis of the insulin signaling cascade. A healthy lean control group was included for muscle morphology and mitochondrial function analyses.ResultsFifty one NAFLD patients were included of whom 43% had NASH. Intramyocellular lipids (IMCL) were associated with the presence of NASH (OR 12.5, p<0.001), progressive hepatic inflammation (p = 0.029) and fibrosis severity (p = 0.010). There was a trend to an association between IMCL and decreased Akt phosphorylation (p = 0.059), despite no association with insulin resistance. In turn, hepatic steatosis (p = 0.015) and inflammation (p = 0.013) were associated with decreased Akt phosphoryation. Citrate synthase activity was lower in obese patients (p = 0.047) whereas complex I (p = 0.040) and III (p = 0.036) activities were higher, compared with controls. Finally, in obese patients, complex I activity increased with progressive steatosis (p = 0.049) and with a trend with fibrosis severity (p = 0.056).ConclusionsIn morbid obese patients, presence of IMCL associates with NASH and advanced fibrosis. Muscle mitochondrial dysfunction does not appear to be a major driving force contributing to muscle fat accumulation, insulin resistance or liver disease. Importantly, insulin resistance in muscle might occur at a late point in the insulin signaling cascade and be associated with IMCL and NAFLD severity.
Highlights
Nonalcoholic fatty liver disease (NAFLD) can be seen as a manifestation of overnutrition
It represents a wide spectrum of pathological subgroups, from benign simple steatosis to nonalcoholic steatohepatitis (NASH), which can progress to hepatic cirrhosis [1], and is associated with overall and liver-related increased mortality [2]
intramyocellular lipids (IMCL) accumulate in athletes, where they are in constant turnover and believed to act as fuel [5], or in association with obesity, insulin resistance/type 2 diabetes mellitus and high fat diets [6,7,8,9]
Summary
Nonalcoholic fatty liver disease (NAFLD) can be seen as a manifestation of overnutrition. IMCL accumulate in athletes, where they are in constant turnover and believed to act as fuel [5], or in association with obesity, insulin resistance/type 2 diabetes mellitus and high fat diets [6,7,8,9]. In this case, lipids are either not consumed or incompletely oxidized, potentially forming dangerous active metabolites that may inhibit the insulin signaling cascade [10,11,12,13,14], further contributing to metabolic disturbances. The up-regulation of triglyceride synthesis was able to protect skeletal muscle from fat-induced insulin resistance in a mouse model [17]
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