fat burning, liver disease, NASH, Uncategorized

FGF21 and NASH

A multi-center FGF21 clinical trial is conducted in the area for the use of a modified fibroblast growth factor 21 for the treatment of NASH  with fibrosis.  What is NASH?

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The progression of fatty liver disease to cirrhosis, or NASH with fibrosis.

What is fibroblast growth factor 21?

Fibroblast Growth Factor 21 (FGF21) is secreted by hepatocytes.  FGF21 stimulates glucose uptake in differentiated adipocytes.  The FGF21 Wikipedia page gives a more fanciful review of the literature concerning FGF21 and behaviors such as the “sweet tooth.”  The protective role of FGF21 are also discussed..

Is FGF21 a signal of liver pathology?

Barb and coworkers of the University of Florida College of Medicine investigated the use of FGF21 as a biomarker of which obese type 2 diabetic patients also had non alcoholic steatohepatitis.   Plasma FGF21 levels were measured in three groups of patients:

  • no non-alcoholic fatty liver disease 325 ± 289 pg/mL
  • patients with borderline NASH or isolated steatosis  341 ± 198 pg/mL
  • definite NASH  453 ± 262 pg/mL

These authors found that Plasma FGF21 correlated with severity of steatohepatitis, especially in the case of NASH patients with  fibrosis.  They proposed use of plasma FGF21 as a biomarker of patients at risk of disease progression.

Can FGF21 be a drug and a biomarker of metabolic problems?

  • In the early days, FGF21 was shown to increase insulin dependent glucose uptake via increasing the expression of the Glut1 glucose transporter in cultured mouse adipocytes.  Sonoda (2017).
  • FGF21 and its receptor FGF21RA induced expression of the Uncoupling protein 1 (UCP1) in primary adipocytes essentially turning fat cells into fat burning machines.
  • In independent studies metabolic benefits to brown adipose tissue were shown to be preserved in mice which lacked the gene for UCP1 suggesting another mechanism(s) of action.
  • A summary of the Schein study (2016) is that in lean  rats, FGF21 shifts lipid disposal into white adipose tissue.  In obese rats, FGF21 shifts lipid disposal into brown, fat burning adipose tissue.
  • In addition to the regulation of brown adipose tissue thermogenesis, Sonoda cite studies indicating that FGF21 can influence the sweet tooth and alcohol by binding to the central nervous system receptor dimer of FGFR1 and β-klotho .
FGF21 may turn white fat to fat burning brown fat.
FGF21, with or or without PEG attached to it, binds to cell membrane receptors that communicate with the nucleus. Messages to produced for proteins like UCP1. UCP1 uncouples burning of fats from ATP production turning mitochondria into fat burning machines.

A Study of Experimental Medication BMS-986036 in Adults With Nonalcoholic Steatohepatitis (NASH) and Stage 3 Liver Fibrosis (FALCON 1)

This is a study of experimental medication BMS-986036,  given to adults with Nonalcoholic Steatohepatitis (NASH; the buildup of fat and inflammation in the liver that is not caused by alcohol) and stage 3 liver fibrosis (severe fibrosis).  BMS-986036 is also known as pegylated FGF21.  The PEG, polyethylene glycol,  is just  a means of increasing the half live of FGF21 in the circulation before it is degraded or excreted in the urine (Sonoda 2017).

Primary Outcome Measures :

  • Proportion of participants who achieve ≥1 stage improvement in fibrosis without worsening of NASH or NASH improvement with no worsening of fibrosis as determined by liver biopsy [ Time Frame: 24 weeks ]
  • NASH Clinical Research Network (CRN) Fibrosis Score [Fibrosis measured on a 0-4 scale: 0 (none); 1 (perisinusoidal or periportal); 2 (perisinusoidal and portal/periportal); 3 (bridging fibrosis); 4 (cirrhosis)] [ Time Frame: 24 weeks
  • NAFLD Activity Score (NAS) [NASH disease activity in the liver measured on a 0-8 scale: unweighted sum of steatosis, or fat (scale: 0-3), lobular inflammation (scale: 0-3), and hepatocellular ballooning (scale: 0-2)] [ Time Frame: 24 weeks ]

References

Barb D, Bril F, Kalavalapalli S, Cusi K.(2019) Plasma Fibroblast Growth Factor 21 Is Associated With Severity of Nonalcoholic Steatohepatitis in Patients With Obesity and Type 2 Diabetes. J Clin Endocrinol Metab.104(8):3327-3336

 

Schlein C, Talukdar S, Heine M, Fischer AW, Krott LM, Nilsson SK, Brenner MB, Heeren J, Scheja L. (2016) FGF21 Lowers Plasma Triglycerides by Accelerating Lipoprotein Catabolism in White and Brown Adipose Tissues. Cell Metab. 2016 Mar 8;23(3):441-53  Free Paper 

Sonoda J, Chen MZ, Baruch A (2017) FGF21-receptor agonists: an emerging therapeutic class for obesity-related disease.  Hormone Molecular Biology and Clinical Investigation. 2017; 20170002  Free Paper

 

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