This article is more than 5 years old. Information may no longer be current.

PPAR-alpha gene may be therapeutic target in NASH

Peroxisome proliferator-activated receptor-alpha gene expression was found to decrease as nonalcoholic fatty liver disease severity increased and increase as nonalcoholic steatohepatitis improved, indicating that the gene may be used as a therapeutic agent for nonalcoholic steatohepatitis, according to published study data.

“Peroxisome proliferator-activated receptor alpha gene have been implicated in non-alcoholic steatohepatitis pathogenesis, mainly based on animal data,” the researchers wrote. “Gene expression data in NASH patients are scarce. We studied liver [PPAR-alpha, beta/delta, and gamma] expression in a large cohort of obese patients assessed for presence of NAFLD at baseline and 1 year follow-up.”

Researchers analyzed data of 125 patients admitted to an obesity clinic between October 2005 and October 2008. Each patient underwent various tests and to determine if NAFLD was present, liver biopsy was performed and then various gene expressions were studied through mRNA quantification.

According to the analysis, a decrease in PPAR-alpha was apparent in the presence of NASH (P = .001). This decrease was also negatively correlated with the increasing grade of steatosis (P = .003), ballooning score (P = .001), the NAFLD Activity Score (NAS; P = .008), NAS-based classification of no NASH, borderline NASH or definite NASH (P = .002) and severity of fibrosis score (P = .003), according to the research.

“The progressive decrease in PPAR-[alpha] expression correlated with the increasing severity for each parameter, the researchers wrote. “There was a tendency for PPAR-[alpha] expression to be lower with increasing levels of inflammation. No significant correlations were found between PPAR-[beta/delta] or PPAR-[gamma] expression and any of the histological features.”

PPAR-alpha expression was found to be positively correlated to adiponectin (P = .010). However, the expression was found to be inversely correlated to visceral fat (P < .001), homeostatic model assessment, insulin resistance (HOMA IR; P < .001) and cytokeratin 18 protein (P = .012).

Multivariate analysis showed the PPAR-alpha gene to be one of the independent, negative predictors of HOMA IR.

Liver PPAR-beta/delta and PPAR-gamma expression did not correlate with any histological feature, glucose metabolism or serum lipids.

At 1 year follow-up, PPAR-alpha expression was “confirmed to correlate with liver histology,” according to the researchers. Longitudinal analysis also confirmed an increase in expression of PPAR-alpha, as well as showing that its target genes were associated with histological improvement (P = .008) in these patients.

“In line with experimental data on the role of [PPAR-alpha] in the pathogenesis of NASH, we show that liver [PPAR-alpha] expression decreases with progressing histological severity of NAFLD and increases in association with NASH improvement, whereas the expression of the other PPARs remain unaltered,” the researchers concluded. – by Melinda Stevens

Disclosures: The researchers report no relevant financial disclosures.