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Whitehead InstituteSex Differences in Health and Disease Seminar Series
February 3, 2020
Sex Differences in the Liver:Metabolism, liver disease and epigenetic
mechanisms
Liver is a Sexually Dimorphic Organ
Yokoyama et al , 2005
Liver fibrosisand cirrhosis
Liver Cancer
Alcoholicliver injury
Autoimmune hepatitis
At the disease level:
Ø Humans show significant sex differences in pharmacokinetics [how the body processes a drug], and pharmacodynamics [how the body responds to a drug], which may impact drug efficacy and safety
Ø This in part reflects sex differences in liver metabolism by both phase I and phase II drug-metabolizing enzymes
• Sex differences in levels of enzymes of liver drug metabolism:P450 metabolism enzymes, drug conjugation enzymes, transporter proteins
At the enzyme (protein) level:
• Sex-differences in levels of enzymes of hepatic steroid and lipid metabolism, contributing to male-biased cardiovascular disease risk
https://translate.bio/rna-therapeutics/
Sex differences in the rate at which certain genes are
transcribed to make their mRNAs
At the mRNA and gene expression level:[how actively a gene is transcribed to make its mRNA]
Sex-differencein rate
The bipotential gonad is directed towards testis development by the SRY gene on the Y chromosome. Testosterone production begins during fetal life, surges at birth, then remains low until puberty. In females, the ovary develops due to the lack of SRY and remains quiescent until puberty, when cyclical estradiol production begins. Genes on the X and Y chromosome are capable of directly controlling sex differences.
Sources of Sex Differences: Hormones vs Chromosomes
Demarest & McCarthy (2015) J Bioenerg Biomembr
Sex Chromosomes
Sex diffs in hypothalamo-pituitary activity at puberty and adulthood
XY
XX Incomplete inactivation
of X-chr genes
Expression ofY-chr genes Direct Chromosomal
Effects onSex Differences
Sex Steroids
1
23 Pituitary
GrowthHormonesecretion
Is it androgen and estrogen? Mostly not (at least, not directly). Only 4% of sex-biased genes are direct functional targets of androgen or estrogen receptors in mouse liver [D Zheng et al, Mol Cell Endo 2018].
Is it chromosomal sex? No, we can masculinize a female liver, and can feminize a male liver, by pituitary hormone administration in animal models.
Is it the sex-specific pattern of pituitary GH secretion? Yes!
Growth and Metabolic EffectsDirect and indirect, some sex-dependent
Pulsatile GHStimulation
HYPOTHALAMO-PITUITARY GH AXIS
Pituitary GH (191 AAs)
production and secretion
-
-+
Neonatal Testosterone programs the male hypothalamus to regulate pituitary
GH release patterns at puberty
Persistent GHStimulation
M F
Sex-specific temporal plasma GH patternsPituitary GH secretion is sex-specific in rats, mice and humans
Waxman DJ et al, PNAS 1991Adams JM et al, Endocrinol 2014Jaffe CA et al, JCI 1998
156
Jaffe et al.
volution-estimated GH secretory patterns are plotted in thebottom panel and the GH concentrations derived from thesesecretion estimates are overlaid on the measured concentra-tion profiles. The mean (
6
SE) GH concentrations for theeight men and eight women are given in Fig. 2. The 24-h pro-files in men were characterized by the presence of a dominantnocturnal pulse with much smaller pulses at other times of theday. In contrast, GH secretion in women was more continuous,with pulses of similar amplitude throughout the 24 h.
Several methods were used to quantify the differences inthe pattern of GH secretion in men and women (Table I). As ameasure of uniformity of pulse amplitude, a SD for each sub-ject’s GH pulse amplitudes during the baseline study was cal-culated. GH pulse amplitudes were logarithmically trans-formed before analysis. This estimate of variation was greaterin men than in women (7.98 vs. 5.31
m
g/liter;
P
5
0.001). Asimilar analysis was performed after logarithmic transforma-tion of the 145 daily GH concentrations. A higher SD for daily
GH was found in men (5.22 vs. 4.03
m
g/liter;
P
5
0.04). Fig. 3shows a histogram of GH concentrations in these two groups.GH concentrations were either equal to or above the assay de-tection limit 98% of the time in men and 100% of the time inwomen. Although there was no difference between men andwomen in terms of absolute GH nadir, there was a differencein the frequency of biologically low GH concentrations. Reu-tens et al. (22) recently reported that subjects with severe or-ganic GH deficiency had virtually all plasma GH concentra-tions
,
0.5
m
g/liter during 24-h sampling. Using this value asan estimate of the minimum GH concentration for bioactivity,only 35
6
4% of the spontaneous plasma GH measurements inmen were above this value, whereas 53
6
6% of the concentra-tions in women exceeded this limit (
P
5
0.04).Deconvolution was used to determine differences in GH
secretion that would account for gender-specific GH concen-tration profiles. Fig. 4 (
top
) shows the BPF for men andwomen calculated as the deconvolution estimated pulse fre-
Figure 2. Composite picture of plasma GH con-centration profiles (mean6SE) in eight men (top) and eight women (bottom) during saline infusions.
156
Jaffe et al.
volution-estimated GH secretory patterns are plotted in thebottom panel and the GH concentrations derived from thesesecretion estimates are overlaid on the measured concentra-tion profiles. The mean (
6
SE) GH concentrations for theeight men and eight women are given in Fig. 2. The 24-h pro-files in men were characterized by the presence of a dominantnocturnal pulse with much smaller pulses at other times of theday. In contrast, GH secretion in women was more continuous,with pulses of similar amplitude throughout the 24 h.
Several methods were used to quantify the differences inthe pattern of GH secretion in men and women (Table I). As ameasure of uniformity of pulse amplitude, a SD for each sub-ject’s GH pulse amplitudes during the baseline study was cal-culated. GH pulse amplitudes were logarithmically trans-formed before analysis. This estimate of variation was greaterin men than in women (7.98 vs. 5.31
m
g/liter;
P
5
0.001). Asimilar analysis was performed after logarithmic transforma-tion of the 145 daily GH concentrations. A higher SD for daily
GH was found in men (5.22 vs. 4.03
m
g/liter;
P
5
0.04). Fig. 3shows a histogram of GH concentrations in these two groups.GH concentrations were either equal to or above the assay de-tection limit 98% of the time in men and 100% of the time inwomen. Although there was no difference between men andwomen in terms of absolute GH nadir, there was a differencein the frequency of biologically low GH concentrations. Reu-tens et al. (22) recently reported that subjects with severe or-ganic GH deficiency had virtually all plasma GH concentra-tions
,
0.5
m
g/liter during 24-h sampling. Using this value asan estimate of the minimum GH concentration for bioactivity,only 35
6
4% of the spontaneous plasma GH measurements inmen were above this value, whereas 53
6
6% of the concentra-tions in women exceeded this limit (
P
5
0.04).Deconvolution was used to determine differences in GH
secretion that would account for gender-specific GH concen-tration profiles. Fig. 4 (
top
) shows the BPF for men andwomen calculated as the deconvolution estimated pulse fre-
Figure 2. Composite picture of plasma GH con-centration profiles (mean6SE) in eight men (top) and eight women (bottom) during saline infusions.
M F
M F
M F
Time of Day (hr)
Hum
anMouse
Rat
Plas
ma
GH
(ng/
ml)
Pulsatile GH vs. Persistent GH Sex difference across species:Sustained GH-free
period in males(pulsatile GH)
vs. persistent GH stimulation in females
Inter-peak interval is key for sexually
dimorphic gene expression:
A minimum GH off-time is required for the male liver
gene expression profile
Liver sex differences emerge at pubertyat onset of strong pituitary GH secretion
Sex-specific steroid hydroxylase P450 mRNAs in rat liver
By which mechanism(s) doesGH regulate sex differences
in liver metabolism?Fundamental biological question:
How does a cell distinguish a pulsatile vs. persistent input signal
Hypothesis: GH regulates Male and Female liver gene transcription by distinct intracellular signaling pathways
GH-Receptor complex
Tyrosinephosphorylation
via JAK2
STAT5GH Pulse-activated Transcription Factor (TF)
Enriched in male liver nuclei; Proposed mediator of male transcription
Waxman et al,J Biol Chem 1995
Anti-pY Western blotof rat liver nuclei
pY-STAT5
1 2 3 4
M M F F
STAT – Signal Transducer andActivator of Transcription
• STAT5 is activated directly, and repeatedly, by each male plasma GH pulse• GH pulses induce STAT5 Tyr-P, nuclear translocation, and DNA binding• Female GH pattern activates liver STAT5 persistently, at a lower level
STAT5 is activated by GH in a sex-dependent manner that
reflects the sex-dependent pattern of pituitary GH stimulation of