Liver, Pancreas and Biliary TractEffects of n-3 polyunsaturated fatty acids in subjects with nonalcoholic fatty liver disease
Introduction
Nonalcoholic fatty liver disease (NAFLD) has become an emergent liver disease and the leading cause of abnormal liver enzymes. The clinical implications of NAFLD are mostly due to its common occurrence in the general population and its potential to progress to cirrhosis, liver failure and hepatocellular carcinoma [1]. Nonalcoholic steatohepatitis (NASH), a subset of NAFLD most commonly associated with progressive liver disease, is characterized by histological features resembling alcohol-induced liver injury (hepatic macrovescicular steatosis with lobular and portal inflammation, nuclear glycogenation). The pathogenesis of NAFLD is still under debate. Its frequent association with obesity, type 2 diabetes (T2DM), dyslipidemia and metabolic syndrome has led to the suggestion that insulin resistance could play a major role [2]. Moreover, several pieces of evidence suggest that a derangement in the capacity to regulate lipid metabolism due to insulin resistance is also present in NAFLD [3]. Increased de novo lipogenesis, accumulation of triglycerides and depletions of long-chain n-3 polyunsaturated fatty acids (PUFAs) have been demonstrated in the hepatic tissue of patients with NAFLD as compared to control subjects [4]. In the setting of metabolic syndrome and insulin resistance, the general reduction of PUFA levels may contribute to the pathogenesis of NAFLD. Indeed, PUFAs are negative controllers of hepatic lipogenesis through the repression of sterol regulatory element-binding protein (SREBP)-1, a transcription factor stimulated by insulin that regulates both the rate of synthesis and the storage of triglycerides in the liver [5]. In addition, it has been demonstrated that PUFAs activate the peroxisome proliferatoractivated receptor-α (PPARα), leading to increased β-oxidation of fatty acids: hence, they can shift the energy balance from storage to consumption [6]. Moreover, PUFAs can reduce the inflammatory status [7] that is supposed to be a key factor in the development and progression from steatosis to more advanced stages of liver damage. Recently, in a model of insulin resistance and NAFLD in rats, it has been shown that the addition of long-chain n-3 polyunsaturated fatty acids reduced tumor necrosis factor-alpha (TNF-α) hepatic levels, restored hepatic PPARα expression and improved fatty liver and the degree of liver damage [8]. In a different study, supply of PUFAs to rats fed a high-fat diet totally prevented insulin resistance in liver and muscle [9]. Few data are available in patients with NAFLD. In a pilot trial, Capanni et al. demonstrated that PUFA supplement improves biochemical and ultrasonographic features of liver steatosis [10]. In this randomized trial, we evaluated whether PUFA treatment improves fatty liver and transaminase levels, and if this improvement is associated with modifications in TNF-α levels and insulin resistance in patients with NAFLD.
Section snippets
Patients
Subjects with non-invasive diagnosis of NAFLD were enrolled in this study. The study design was approved by the ethics committee of the Hospital. The diagnosis of NAFLD was established on the basis of the following features: an increase in alanine aminotransferase (ALT) levels for ≥6 months before the study, ultrasonography demonstrating fatty liver, negative diagnostic tests for viral hepatitis (completely negative hepatitis B and C serologies for current or past exposure), absence of features
Results
A total of 40 patients were enrolled. After randomization, two patients in the group given dietary treatment (D group) left the study because they did not attend control visits regularly, and two patients in the group with diet plus PUFA treatment (DP group) left the study for the following reasons: one patient was not compliant with the therapy and one patient moved to a different city. Therefore, 36 patients completed the protocol and were included in the analysis. The baseline clinical and
Discussion
In this randomized trial, we showed that in NAFLD patients, PUFA treatment reduced liver fat content and alanine aminotransferase levels, decreased TNF-α serum levels and improved insulin resistance. No pharmacologic therapy has conclusively proved to be effective for the treatment of NAFLD, as the current management is directed towards the treatment of associated metabolic conditions. Since insulin resistance is frequently associated with NAFLD and plays a key role in lipid accumulation within
Conflict of interest statement
None declared.
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