Testosterone suppresses the expression of regulatory enzymes of fatty acid synthesis and protects against hepatic steatosis in cholesterol-fed androgen deficient mice

Daniel M. Kelly, Joanne E. Nettleship, Samia Akhtar, Vakkat Muraleedharan, Donna J. Sellers, Jonathan C. Brooke, David S. McLaren, Kevin S. Channer, T. Hugh Jones

Research output: Contribution to journalArticleResearchpeer-review

33 Citations (Scopus)

Abstract

Aims: Non-alcoholic fatty liver disease and its precursor hepatic steatosis is common in obesity and type-2 diabetes and is associatedwith cardiovascular disease (CVD).Men with type-2 diabetes and/or CVD have a high prevalence of testosterone deficiency. Testosterone replacement improves key cardiovascular risk factors. The effects of testosterone on hepatic steatosis are not fully understood.

Main methods: Testicular feminised (Tfm) mice, which have a non-functional androgen receptor (AR) and very lowserumtestosterone levels,were used to investigate testosterone effects on high-cholesterol diet-induced hepatic steatosis.

Key findings: Hepatic lipid deposition was increased in Tfmmice and orchidectomised wild-type littermates versus intact wild-type littermate controls with normal androgen physiology. Lipid deposition was reduced in Tfm mice receiving testosterone treatment compared to placebo. Oestrogen receptor blockade significantly, but only partially, reduced the beneficial effects of testosterone treatment on hepatic lipid accumulation. Expression of key regulatory enzymes of fatty acid synthesis, acetyl-CoA carboxylase alpha (ACACA) and fatty acid synthase (FASN) were elevated in placebo-treated Tfm mice versus placebo-treated littermates and Tfm mice receiving testosterone treatment. Tfm mice on normal diet had increased lipid accumulation compared to littermates but significantly less than cholesterol-fed Tfm mice and demonstrated increased gene expression of hormone sensitive lipase, stearyl-CoA desaturase-1 and peroxisome proliferator-activated receptor-gamma but FASN and ACACA were not altered.

Significance: An action of testosterone on hepatic lipid deposition which is independent of the classic AR is implicated. Testosteronemay act in part via an effect on the key regulatory lipogenic enzymes to protect against hepatic steatosis.

Original languageEnglish
Pages (from-to)95-103
Number of pages9
JournalLife Sciences
Volume109
Issue number2
DOIs
Publication statusPublished - 30 Jul 2014

Fingerprint

Androgens
Testosterone
Fatty Acids
Cholesterol
Liver
Enzymes
Lipids
Acetyl-CoA Carboxylase
Fatty Acid Synthases
Placebos
Androgen Receptors
Nutrition
Medical problems
Type 2 Diabetes Mellitus
Cardiovascular Diseases
Stearoyl-CoA Desaturase
Diet
Sterol Esterase
PPAR gamma
Physiology

Cite this

Kelly, Daniel M. ; Nettleship, Joanne E. ; Akhtar, Samia ; Muraleedharan, Vakkat ; Sellers, Donna J. ; Brooke, Jonathan C. ; McLaren, David S. ; Channer, Kevin S. ; Jones, T. Hugh. / Testosterone suppresses the expression of regulatory enzymes of fatty acid synthesis and protects against hepatic steatosis in cholesterol-fed androgen deficient mice. In: Life Sciences. 2014 ; Vol. 109, No. 2. pp. 95-103.
@article{839a36ec2ba7425b8a98d4eb2d3fad3f,
title = "Testosterone suppresses the expression of regulatory enzymes of fatty acid synthesis and protects against hepatic steatosis in cholesterol-fed androgen deficient mice",
abstract = "Aims: Non-alcoholic fatty liver disease and its precursor hepatic steatosis is common in obesity and type-2 diabetes and is associatedwith cardiovascular disease (CVD).Men with type-2 diabetes and/or CVD have a high prevalence of testosterone deficiency. Testosterone replacement improves key cardiovascular risk factors. The effects of testosterone on hepatic steatosis are not fully understood.Main methods: Testicular feminised (Tfm) mice, which have a non-functional androgen receptor (AR) and very lowserumtestosterone levels,were used to investigate testosterone effects on high-cholesterol diet-induced hepatic steatosis.Key findings: Hepatic lipid deposition was increased in Tfmmice and orchidectomised wild-type littermates versus intact wild-type littermate controls with normal androgen physiology. Lipid deposition was reduced in Tfm mice receiving testosterone treatment compared to placebo. Oestrogen receptor blockade significantly, but only partially, reduced the beneficial effects of testosterone treatment on hepatic lipid accumulation. Expression of key regulatory enzymes of fatty acid synthesis, acetyl-CoA carboxylase alpha (ACACA) and fatty acid synthase (FASN) were elevated in placebo-treated Tfm mice versus placebo-treated littermates and Tfm mice receiving testosterone treatment. Tfm mice on normal diet had increased lipid accumulation compared to littermates but significantly less than cholesterol-fed Tfm mice and demonstrated increased gene expression of hormone sensitive lipase, stearyl-CoA desaturase-1 and peroxisome proliferator-activated receptor-gamma but FASN and ACACA were not altered.Significance: An action of testosterone on hepatic lipid deposition which is independent of the classic AR is implicated. Testosteronemay act in part via an effect on the key regulatory lipogenic enzymes to protect against hepatic steatosis.",
author = "Kelly, {Daniel M.} and Nettleship, {Joanne E.} and Samia Akhtar and Vakkat Muraleedharan and Sellers, {Donna J.} and Brooke, {Jonathan C.} and McLaren, {David S.} and Channer, {Kevin S.} and Jones, {T. Hugh}",
year = "2014",
month = "7",
day = "30",
doi = "10.1016/j.lfs.2014.06.007",
language = "English",
volume = "109",
pages = "95--103",
journal = "Life sciences. Pt. 2: Biochemistry, general and molecular biology",
issn = "0024-3205",
publisher = "Elsevier",
number = "2",

}

Testosterone suppresses the expression of regulatory enzymes of fatty acid synthesis and protects against hepatic steatosis in cholesterol-fed androgen deficient mice. / Kelly, Daniel M.; Nettleship, Joanne E.; Akhtar, Samia; Muraleedharan, Vakkat; Sellers, Donna J.; Brooke, Jonathan C.; McLaren, David S.; Channer, Kevin S.; Jones, T. Hugh.

In: Life Sciences, Vol. 109, No. 2, 30.07.2014, p. 95-103.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Testosterone suppresses the expression of regulatory enzymes of fatty acid synthesis and protects against hepatic steatosis in cholesterol-fed androgen deficient mice

AU - Kelly, Daniel M.

AU - Nettleship, Joanne E.

AU - Akhtar, Samia

AU - Muraleedharan, Vakkat

AU - Sellers, Donna J.

AU - Brooke, Jonathan C.

AU - McLaren, David S.

AU - Channer, Kevin S.

AU - Jones, T. Hugh

PY - 2014/7/30

Y1 - 2014/7/30

N2 - Aims: Non-alcoholic fatty liver disease and its precursor hepatic steatosis is common in obesity and type-2 diabetes and is associatedwith cardiovascular disease (CVD).Men with type-2 diabetes and/or CVD have a high prevalence of testosterone deficiency. Testosterone replacement improves key cardiovascular risk factors. The effects of testosterone on hepatic steatosis are not fully understood.Main methods: Testicular feminised (Tfm) mice, which have a non-functional androgen receptor (AR) and very lowserumtestosterone levels,were used to investigate testosterone effects on high-cholesterol diet-induced hepatic steatosis.Key findings: Hepatic lipid deposition was increased in Tfmmice and orchidectomised wild-type littermates versus intact wild-type littermate controls with normal androgen physiology. Lipid deposition was reduced in Tfm mice receiving testosterone treatment compared to placebo. Oestrogen receptor blockade significantly, but only partially, reduced the beneficial effects of testosterone treatment on hepatic lipid accumulation. Expression of key regulatory enzymes of fatty acid synthesis, acetyl-CoA carboxylase alpha (ACACA) and fatty acid synthase (FASN) were elevated in placebo-treated Tfm mice versus placebo-treated littermates and Tfm mice receiving testosterone treatment. Tfm mice on normal diet had increased lipid accumulation compared to littermates but significantly less than cholesterol-fed Tfm mice and demonstrated increased gene expression of hormone sensitive lipase, stearyl-CoA desaturase-1 and peroxisome proliferator-activated receptor-gamma but FASN and ACACA were not altered.Significance: An action of testosterone on hepatic lipid deposition which is independent of the classic AR is implicated. Testosteronemay act in part via an effect on the key regulatory lipogenic enzymes to protect against hepatic steatosis.

AB - Aims: Non-alcoholic fatty liver disease and its precursor hepatic steatosis is common in obesity and type-2 diabetes and is associatedwith cardiovascular disease (CVD).Men with type-2 diabetes and/or CVD have a high prevalence of testosterone deficiency. Testosterone replacement improves key cardiovascular risk factors. The effects of testosterone on hepatic steatosis are not fully understood.Main methods: Testicular feminised (Tfm) mice, which have a non-functional androgen receptor (AR) and very lowserumtestosterone levels,were used to investigate testosterone effects on high-cholesterol diet-induced hepatic steatosis.Key findings: Hepatic lipid deposition was increased in Tfmmice and orchidectomised wild-type littermates versus intact wild-type littermate controls with normal androgen physiology. Lipid deposition was reduced in Tfm mice receiving testosterone treatment compared to placebo. Oestrogen receptor blockade significantly, but only partially, reduced the beneficial effects of testosterone treatment on hepatic lipid accumulation. Expression of key regulatory enzymes of fatty acid synthesis, acetyl-CoA carboxylase alpha (ACACA) and fatty acid synthase (FASN) were elevated in placebo-treated Tfm mice versus placebo-treated littermates and Tfm mice receiving testosterone treatment. Tfm mice on normal diet had increased lipid accumulation compared to littermates but significantly less than cholesterol-fed Tfm mice and demonstrated increased gene expression of hormone sensitive lipase, stearyl-CoA desaturase-1 and peroxisome proliferator-activated receptor-gamma but FASN and ACACA were not altered.Significance: An action of testosterone on hepatic lipid deposition which is independent of the classic AR is implicated. Testosteronemay act in part via an effect on the key regulatory lipogenic enzymes to protect against hepatic steatosis.

UR - http://www.scopus.com/inward/record.url?scp=84907018967&partnerID=8YFLogxK

U2 - 10.1016/j.lfs.2014.06.007

DO - 10.1016/j.lfs.2014.06.007

M3 - Article

VL - 109

SP - 95

EP - 103

JO - Life sciences. Pt. 2: Biochemistry, general and molecular biology

JF - Life sciences. Pt. 2: Biochemistry, general and molecular biology

SN - 0024-3205

IS - 2

ER -