Glitazone class drugs and fibrosis

[Guest guest]

This is sort of aimed at , or anyone else who can fill me in.

This class of drugs, the glitazones, are used in diabetes and one of

them was recently approved to treat non-alcoholic steato-hepatitis

(NASH), a fatty liver disease that also causes fibrosis. They activate

a nuclear receptor, PPAR-gamma, that improves insulin sensitivity,

among other things. The literature seems to suggest that it can

actually reverse fibrosis in the liver. Could non-diabetics be

treated with these drugs? Is anyone working on them in PSC?

I see that safety is also an issue because the first one,

troglitazone, was withdrawn from the market due to hepatotoxicity.

Not so good! The remaining ones are supposed to be better but there

seem to be sporadic cases of hepatotoxicity for one of the others as

well. Apparently curcumin, a chemical in turmeric, also activates

PPAR-gamma in vitro, but hasn't worked in vivo. Hmm, I love Indian food!

I'd like to read the review below but my university library doesn't

have access rights. I can get it by ILL eventually.

Martha (MA)

Hepatol Res. 2005 Sep 28; [Epub ahead of print]

Thiazolidinediones: Pleiotropic drugs with potent

anti-inflammatory properties for tissue protection.

Buckingham RE.

Department of Diabetes, Endocrinology and Internal Medicine,

King's College and Guy's Hospital, 5th Floor Guy House, KCL

Guy's Campus, London SE1 9RT, UK.

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a

nuclear transcription factor that comprises the primary molecular

target for thiazolidinedione (TZD) insulin-sensitizing drugs. Whilst

expressed in many tissues in humans, its abundant expression in

adipose tissue is believed to be the focal point through which TZDs

regulate genes involved in glucose and lipid metabolism and via which

these agents ultimately improve the hyperglycemia of type 2 diabetes.

However, TZDs exhibit many additional properties, not least an array

of effects which suggest a broad attack on the inflammatory process.

Thus, TZDs have been shown to reduce plasma levels of the chemokine,

monocyte chemotactic protein-1 (MCP-1), the anti-fibrinolytic protein,

plasminogen activator inhibitor-1 (PAI-1), the endothelial cell

adhesion molecules, e-selectin and inter-cellular adhesion molecule-1

(ICAM-1), the leucocyte-activating molecule, CD40L, and the

tissue-remodeling enzyme, matrix metalloproteinase-9 (MMP-9). Further

tangible evidence of a reduction by TZDs of systemic inflammation in

patients with the classical metabolic syndrome stems from falls in the

white blood cell count, P-selectin-positive platelets and in the

acute-phase inflammatory proteins, C-reactive protein, serum amyloid A

and fibrinogen. At the tissue level, TZDs improve vascular endothelial

function, and reduce the rate of progression of intimal-medial

thickening of the carotid artery and the microalbuminuria of type 2

diabetes. Further, TZDs have been shown to be efficacious in

inflammatory diseases as wide-ranging as psoriasis, ulcerative colitis

and non-alcoholic steatohepatitis (NASH). In the case of the latter, a

broad spectrum of TZD-related properties is visible. Here, these drugs

improve insulin sensitivity for glucose metabolism, reduce

hyperinsulinemia, hepatic steatosis, inflammation and fibrosis, and

lower the circulating levels of liver transaminases (ALT, AST),

alkaline phosphatase and gamma glutamyl transferase. These effects in

humans are also well-supported by investigative animal and in vitro

studies. The ameliorative effects on liver fibrosis are of particular

interest since they suggest that TZDs are able to activate a program

of corrective tissue-remodeling. The basis for this action may be

partly an ability to inhibit matrix protein secretion by hepatic

stellate cells. An analogous action has also been seen in kidney

mesangial cells. In conclusion, TZDs are important new drugs,

presently indicated for the treatment of type 2 diabetes but with a

spectrum of properties which suggests their potential for treating a

number of degenerative inflammatory diseases, including NASH. However,

full-scale, long-term clinical trials are needed with TZDs to test

their potential to treat NASH, not least because of the (hepatotoxic)

legacy of the prototype TZD, troglitazone, but also in view of the

escalating burden of liver disease which is accompanying the

increasing global prevalence of clinical obesity and type 2 diabetes.