Atorvastatin and Vitamin E Accelerates NASH Resolution by Dietary Intervention in a Preclinical Guinea Pig Model

Abstract

Despite affecting millions of patients worldwide, no pharmacological treatment has yet proved effective against non-alcoholic steatohepatitis (NASH) induced liver fibrosis. Current guidelines recommend lifestyle modifications including reductions in dietary energy intake. Recently, therapy with atorvastatin and vitamin E (vitE) has been recommended, although clinical studies on the resolution of hepatic fibrosis are inconclusive. Targeting NASH-induced hepatic end-points, this study evaluated the effects of atorvastatin and vitE alone or in combination with a dietary intervention in the guinea pig NASH model. Guinea pigs (n = 72) received 20 weeks of high fat feeding before allocating to four groups: continued HF feeding (HF), HF diet with atorvastatin and vitE (HF+), low-fat diet (LF) and low-fat with atorvastatin and vitE (LF+), for four or eight weeks of intervention. Both LF and LF+ decreased liver weight, cholesterol and plasma dyslipidemia. LF+ further improved hepatic histopathological hallmarks (p < 0.05), liver injury markers aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (p < 0.05) and reduced the expression of target genes of hepatic inflammation and fibrosis (p < 0.05), underlining an increased effect on NASH resolution in this group. Collectively, the data support an overall beneficial effect of diet change, and indicate that atorvastatin and vitE therapy combined with a diet change act synergistically in improving NASH-induced endpoints.

Dietary Intervention Accelerates NASH Resolution Depending on Inflammatory Status with Minor Additive Effects on Hepatic Injury by Vitamin E Supplementation

“…On the other hand, results on the effects of vitE therapy on hepatic fibrosis regression has not been conclusive. A positive trend towards fibrosis regression was observed in the preclinical guinea pig model subjected to vitE (800 IU/d) and atorvastatin (1 mg/kg) treatment, mimicking the doses applied in humans [20,28,34]. In this study, vitE and atorvastatin treatment combined with dietary intervention resulted in an increased effect on ballooning hepatocytes, lobular inflammation and fibrosis compared with dietary intervention alone [20].…”

“…Embedded tissue was subsequently sectioned in 2-4 µm thick slices. For histopathological examination of steatosis, lobular inflammation and ballooning hepatocytes sections were stained with haematoxylin and eosin and picro sirius red for evaluation of fibrosis [20]. Liver slides were scored in a blinded fashion using a semiquantitative scoring system based on the methodology developed by Kleiner et al [43].…”

“…Portal inflammation was graded as 0 (not present) or 1 (present), with presence defined as ≥2 portal areas containing ≥2 foci, with foci defined as ≥5 inflammatory cells. Finally, the NAFLD activity score (NAS) was calculated consisting of the sum of steatosis grade, lobular inflammation grade and ballooning hepatocyte grade, with a range between a minimum of 0 and a maximum score of 8 [20,43].…”

Maternal N-Acetyl Cysteine Intake Improved Glucose Tolerance in Obese Mice Offspring

“…NAC was given to female C57bl6/J mice (F 0 ) during pregnancy and lactation and HFD was given to 6 week old offspring (F 1 ). Body weight accumulation in F1 mice was measured: a higher body weight gain was found in HFD-fed compared to standard diet (STD)-fed mice, in both male and female, with males found to have higher body weight gain than females.…”

“…Oxidative stress is one of these diabetogenic factors, which has a central role in the development and progression of T2D and its associated comorbidities [4,5]. Antioxidant therapy, such as the administration of vitamin E or pentoxifylline, neutralized oxidative stress, improved glucose homeostasis and reduced the severity of nonalcoholic steatohepatitis (NASH) [6][7][8].…”