Nonalcoholic fatty liver disease (
NAFLD) is associated with
obesity,
insulin resistance, and inflammatory disorders. In this study, we tested the effect of
rhein, a lipophilic
anthraquinone derived from a traditional Chinese herbal medicine Rheum palmatum L., on
NAFLD-associated hepatic steatosis,
insulin resistance, and the T helper (Th)1/Th2
cytokine imbalance in high-fat diet-induced obese (DIO) mice. We found that
oral administration of
rhein for 40 days significantly increased energy expenditure, reduced
body weight, particularly body fat content, improved
insulin resistance, and lowered circulating
cholesterol levels in DIO mice without affecting food intake.
Rhein treatment also reduced liver
triglyceride levels, reversed hepatic steatosis, and normalized
alanine aminotransferase (ALT) levels in these mice. Gene analysis and Western blot showed that
rhein markedly suppressed the expression of the lipogenic
enzyme sterol regulatory
element-binding protein-1c (SREBP-1c) and its target genes in the liver.
Luciferase reporter assay revealed that
rhein suppressed the transcriptional activity of
SREBP-1c through its upstream regulator,
liver X receptor (LXR). This suggests that
rhein exerts its effects by targeting LXR, which is also supported by its inability to reduce
body weight in LXR knockout mice. Moreover, multiplex ELISA displayed a downregulated Th1 response after
rhein treatment.
Rhein shifted the Th1/Th2 responses by inhibiting T-box expressed in T-cells (T-bet) expression and enhancing GATA-binding protein-3 (GATA-3) expression through increased
signal transducer and activator of transcription 6 (STAT6) phosphorylation. These data indicate that
rhein ameliorated
NAFLD and associated disorders through LXR-mediated negative energy balance, metabolic regulatory pathways, and immunomodulatory activities involved in hepatic steatosis. The combined effects of
rhein to target hepatic metabolic and immune pathways may be beneficial for complex
metabolic diseases such as
NAFLD.