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PROFESSOR: We're now
at storyboard 23.

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00:00:23,280 --> 00:00:26,550
Let's look at panel
A. Our last metabolism

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00:00:26,550 --> 00:00:31,140
topic under the general umbrella
of catabolism is ketone bodies.

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00:00:31,140 --> 00:00:34,140
Ketone bodies are only covered
in two pages in the book,

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00:00:34,140 --> 00:00:36,230
but they're medically
very important.

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00:00:36,230 --> 00:00:38,500
The medical relevance
of ketone bodies

14
00:00:38,500 --> 00:00:40,770
stems from their
role in starvation

15
00:00:40,770 --> 00:00:42,870
and their role in diabetes.

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00:00:42,870 --> 00:00:47,340
Let's look at panel A. This
panel shows various sources of

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00:00:47,340 --> 00:00:49,680
and uses of acetyl CoA.

18
00:00:49,680 --> 00:00:53,280
It shows that ketone bodies are
made from Acetyl coenzyme A.

19
00:00:53,280 --> 00:00:55,680
So let's start this
part of the lecture

20
00:00:55,680 --> 00:00:59,280
with a discussion of where
acetyl CoA comes from,

21
00:00:59,280 --> 00:01:01,140
and what its various
states are including

22
00:01:01,140 --> 00:01:03,330
the formation of ketone bodies.

23
00:01:03,330 --> 00:01:06,610
We just finished talking
about fatty acid catabolism.

24
00:01:06,610 --> 00:01:08,950
So let's start on the
right of this figure.

25
00:01:08,950 --> 00:01:11,085
We see that a fatty
acid can be broken down

26
00:01:11,085 --> 00:01:14,130
to form acetyl CoA
by beta oxidation,

27
00:01:14,130 --> 00:01:17,040
usually with the objective
of generating energy.

28
00:01:17,040 --> 00:01:19,890
If we follow the acetyl
CoA from beta oxidation

29
00:01:19,890 --> 00:01:22,380
down into the TCA
cycle, we see that it

30
00:01:22,380 --> 00:01:25,650
will be fully oxidized to carbon
dioxide with the generation

31
00:01:25,650 --> 00:01:27,510
of a lot of energy
that can be used

32
00:01:27,510 --> 00:01:30,840
for mechanical work,
biosynthesis, and other things.

33
00:01:30,840 --> 00:01:32,730
A second source
of Acetyl CoA can

34
00:01:32,730 --> 00:01:34,620
be seen to the
left, where we see

35
00:01:34,620 --> 00:01:37,050
glycogen breakdown
to glucose or glucose

36
00:01:37,050 --> 00:01:39,480
can be directly
imported into a cell.

37
00:01:39,480 --> 00:01:42,330
In either case, the glucose
that we take in or liberate

38
00:01:42,330 --> 00:01:44,100
from its storage
depot, glycogen,

39
00:01:44,100 --> 00:01:47,580
can be converted into
acetyl coenzyme A.

40
00:01:47,580 --> 00:01:50,070
Glycerol can be generated
from the backbone

41
00:01:50,070 --> 00:01:52,950
of a metabolized
triacylglyceride.

42
00:01:52,950 --> 00:01:56,310
It enters glycolysis as
dihydroxyacetone phosphate

43
00:01:56,310 --> 00:02:00,840
and then can progress to acetyl
CoA by way of glycolysis.

44
00:02:00,840 --> 00:02:04,050
Alanine can transiminate
into pyruvate,

45
00:02:04,050 --> 00:02:06,300
which is converted
subsequently to acetyl CoA

46
00:02:06,300 --> 00:02:08,910
by pyruvate dehydrogenase.

47
00:02:08,910 --> 00:02:12,480
This diagram shows us that
many pathways converge

48
00:02:12,480 --> 00:02:17,130
to generate acetyl coenzyme
A. Carbohydrates, amino acids,

49
00:02:17,130 --> 00:02:19,290
fatty acids, all
can act as a source

50
00:02:19,290 --> 00:02:22,980
of this important
precursor to energy.

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00:02:22,980 --> 00:02:26,890
Aside from being processed by
the TCA cycle, on the left,

52
00:02:26,890 --> 00:02:28,980
we see a broken line
pathway involving

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00:02:28,980 --> 00:02:31,050
fatty acid biosynthesis.

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00:02:31,050 --> 00:02:33,060
This is going to be the
next topic we come to

55
00:02:33,060 --> 00:02:36,660
after this discussion of
ketone body formation.

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00:02:36,660 --> 00:02:39,030
The pathway on the right
with the broken lines

57
00:02:39,030 --> 00:02:41,490
is the pathway leading
to ketone bodies

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00:02:41,490 --> 00:02:43,740
which is called ketogenesis.

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00:02:43,740 --> 00:02:46,770
In the box at the top of panel
A is a cartoon reminding me

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00:02:46,770 --> 00:02:49,980
to tell you that acetyl CoA
cannot escape from the cell.

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00:02:49,980 --> 00:02:54,300
Moreover, it cannot even easily
escape from the mitochondrion.

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00:02:54,300 --> 00:02:56,430
In order for acetyl
CoA to leave the cell

63
00:02:56,430 --> 00:02:58,515
and be transported from
one organ to another,

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00:02:58,515 --> 00:03:00,990
it needs to be converted
into ketone bodies.

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00:03:00,990 --> 00:03:02,850
Another way to look
at ketone bodies

66
00:03:02,850 --> 00:03:05,160
is that these are
mobile or portable forms

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00:03:05,160 --> 00:03:08,700
of Acetyl CoA that can go from
a source organ, which is usually

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00:03:08,700 --> 00:03:12,000
the liver, to a target organ,
which may need them in order

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00:03:12,000 --> 00:03:15,030
to generate energy by
way of the TCA cycle.

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00:03:15,030 --> 00:03:17,130
The target organ for
example could be brain

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00:03:17,130 --> 00:03:18,855
under conditions of
starvation, or it

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00:03:18,855 --> 00:03:20,400
could be skeletal
muscle if you have

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00:03:20,400 --> 00:03:22,560
to run away from something.

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00:03:22,560 --> 00:03:25,740
Let's look at panel B. There
are five key facts that we need

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00:03:25,740 --> 00:03:27,570
to know about ketone bodies.

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00:03:27,570 --> 00:03:30,600
First, Ketogenesis mainly
occurs in the liver.

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00:03:30,600 --> 00:03:32,670
The liver manufactures
ketone bodies

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00:03:32,670 --> 00:03:36,090
and then exports them
to other organs for use.

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00:03:36,090 --> 00:03:39,810
These reactions typically happen
when the levels of oxaloacetate

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00:03:39,810 --> 00:03:42,210
become limiting in
their mitochondrion.

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00:03:42,210 --> 00:03:43,740
And I'll give you
an example of why

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00:03:43,740 --> 00:03:46,470
this is the case when I talk
about starvation a little later

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00:03:46,470 --> 00:03:47,370
in this lecture.

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00:03:47,370 --> 00:03:49,860
The second important
fact is that these

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00:03:49,860 --> 00:03:52,770
are the primary metabolic
fuels of the heart and skeletal

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00:03:52,770 --> 00:03:55,110
muscle under normal conditions.

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00:03:55,110 --> 00:03:56,850
The third fact is
that ketone bodies

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00:03:56,850 --> 00:04:00,000
become the major metabolic
fuel of all cells

89
00:04:00,000 --> 00:04:01,920
under conditions
of starvation, even

90
00:04:01,920 --> 00:04:04,710
cells of the brain after
a few days of starvation

91
00:04:04,710 --> 00:04:07,920
will convert from glucose being
the preferred metabolic fuel

92
00:04:07,920 --> 00:04:11,370
to accepting ketone bodies as
their major source of energy.

93
00:04:11,370 --> 00:04:13,500
The fourth fact I want
to talk about with regard

94
00:04:13,500 --> 00:04:14,910
to ketone bodies
is that they are

95
00:04:14,910 --> 00:04:17,519
produced in excess in diabetes.

96
00:04:17,519 --> 00:04:19,320
I'll talk a little
bit more about that

97
00:04:19,320 --> 00:04:20,910
later in the lecture.

98
00:04:20,910 --> 00:04:24,810
Finally, ketogenesis occurs in
the mitochondrion, primarily

99
00:04:24,810 --> 00:04:26,520
the mitochondrion of the liver.

100
00:04:26,520 --> 00:04:29,550
So these are
mitochondrial reactions.

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00:04:29,550 --> 00:04:33,240
Panel C shows the three
classical ketone bodies,

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00:04:33,240 --> 00:04:36,990
acetoacetate, beta
hydroxybutyrate, and acetone.

103
00:04:36,990 --> 00:04:39,090
From the standpoint
of chemical accuracy,

104
00:04:39,090 --> 00:04:41,670
it's obvious that
beta hydroxybutyrate

105
00:04:41,670 --> 00:04:43,590
is an alcohol and not a ketone.

106
00:04:43,590 --> 00:04:46,500
Nevertheless, it's lumped
in with the ketone bodies

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00:04:46,500 --> 00:04:48,130
for historical reasons.

108
00:04:48,130 --> 00:04:50,640
Acetoacetate and
beta hydroxybutyrate

109
00:04:50,640 --> 00:04:52,890
are what I'll call quote
unquote "useful" ketone

110
00:04:52,890 --> 00:04:55,410
bodies from the standpoint
of serving as precursors

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00:04:55,410 --> 00:04:57,000
to metabolic energy.

112
00:04:57,000 --> 00:05:00,930
Acetone by contrast, is not
useful by this criterion.

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00:05:00,930 --> 00:05:04,620
Acetone however, is
a useful biomarker,

114
00:05:04,620 --> 00:05:08,340
because sometimes its presence
can help diagnose diabetes.

115
00:05:08,340 --> 00:05:11,730
On a personal note, I come
from a long line of diabetics.

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00:05:11,730 --> 00:05:14,760
I remember when I was a
little kid, my dad before he

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00:05:14,760 --> 00:05:16,530
was diagnosed, would
come home from work

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00:05:16,530 --> 00:05:18,090
at the end of the day.

119
00:05:18,090 --> 00:05:19,650
He had very poor circulation.

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00:05:19,650 --> 00:05:21,510
So my two sisters
and I would try

121
00:05:21,510 --> 00:05:24,030
to rub his legs to give
him a kind of massage

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00:05:24,030 --> 00:05:26,490
to make his circulation
a little bit better.

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00:05:26,490 --> 00:05:30,940
I remember very clearly my
older sister saying, "gee,

124
00:05:30,940 --> 00:05:34,560
dad smells like mom's
nail polish remover,"

125
00:05:34,560 --> 00:05:37,140
and that's because he
was a diabetic producing

126
00:05:37,140 --> 00:05:39,540
acetone, which was used
at the time at least

127
00:05:39,540 --> 00:05:41,280
as nail polish remover.

128
00:05:41,280 --> 00:05:44,130
We had no idea at the
time what was going on.

129
00:05:44,130 --> 00:05:47,730
A few months later, my dad was
diagnosed as a type 2 diabetic.

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00:05:47,730 --> 00:05:50,790
I now know that the fruity
odor we smelled on his breath

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00:05:50,790 --> 00:05:52,140
was acetone.

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00:05:52,140 --> 00:05:56,640
As I said, acetone is a
biomarker of this disease.

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00:05:56,640 --> 00:05:59,370
One last point with
regard to the story board.

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00:05:59,370 --> 00:06:03,750
Note that the acetoacetate and
beta hydroxybutyrate molecules

135
00:06:03,750 --> 00:06:05,010
are acids.

136
00:06:05,010 --> 00:06:07,200
In diabetics, these
acids can be produced

137
00:06:07,200 --> 00:06:09,900
as we'll see later
in sufficiently

138
00:06:09,900 --> 00:06:12,840
high concentrations to
lower the pH of the blood

139
00:06:12,840 --> 00:06:14,940
quite substantially.

140
00:06:14,940 --> 00:06:17,070
Keep in mind that
lowering the pH

141
00:06:17,070 --> 00:06:20,010
is the same thing as increasing
the concentration of protons

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00:06:20,010 --> 00:06:21,760
in the blood.

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00:06:21,760 --> 00:06:25,050
These concentrated protons will
have physiological relevance

144
00:06:25,050 --> 00:06:26,730
that I'll discuss later.

145
00:06:26,730 --> 00:06:29,730
When a diabetic enters the phase
where the pH of their blood

146
00:06:29,730 --> 00:06:34,080
is dangerously low, that's
called diabetic acidosis.

147
00:06:34,080 --> 00:06:36,630
Let's now turn to
Panel D. At this point

148
00:06:36,630 --> 00:06:39,780
I want to describe the detailed
biochemical reactions that

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00:06:39,780 --> 00:06:41,820
give rise to ketone bodies.

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00:06:41,820 --> 00:06:43,320
To make a ketone
body we're going

151
00:06:43,320 --> 00:06:45,816
to need three molecules
of acetyl coenzyme

152
00:06:45,816 --> 00:06:48,660
A. One of these molecules
is going to be catalytic.

153
00:06:48,660 --> 00:06:51,960
That is, it's going to be
restored at the overall end

154
00:06:51,960 --> 00:06:54,270
of the process of ketogenesis.

155
00:06:54,270 --> 00:06:56,520
Let's start by
imagining a scenario

156
00:06:56,520 --> 00:06:58,770
in the mitochondrion
of a liver cell

157
00:06:58,770 --> 00:07:01,230
where oxaloacetate
becomes limiting.

158
00:07:01,230 --> 00:07:04,770
I'll talk about physiological
states under which oxaloacetate

159
00:07:04,770 --> 00:07:08,410
becomes limiting or
sparse a little bit later.

160
00:07:08,410 --> 00:07:11,130
Acetyl CoA cannot
enter the TCA cycle,

161
00:07:11,130 --> 00:07:15,000
because citrate synthase lacks
oxaloacetate as a reaction

162
00:07:15,000 --> 00:07:16,200
partner.

163
00:07:16,200 --> 00:07:20,080
The concentration of acetyl
CoA starts to accumulate.

164
00:07:20,080 --> 00:07:22,680
Then the beta
ketothiolase reaction

165
00:07:22,680 --> 00:07:27,330
that is the last step in
fatty acid bio oxidation

166
00:07:27,330 --> 00:07:31,515
reverses owing to the high
concentration of product acetyl

167
00:07:31,515 --> 00:07:32,730
CoA.

168
00:07:32,730 --> 00:07:35,790
So two acetyl CoAs
come together in order

169
00:07:35,790 --> 00:07:39,330
to form acetoacetyl
coenzyme A. Note

170
00:07:39,330 --> 00:07:41,610
that I put markers on
each of the carbons

171
00:07:41,610 --> 00:07:45,980
of the acetoacetyl coenzyme A.
A third acetoacetyl coenzyme

172
00:07:45,980 --> 00:07:48,720
A is then added to
the gamma carbon

173
00:07:48,720 --> 00:07:52,680
of the acetoacetyl coenzyme
A. That's the carbon that

174
00:07:52,680 --> 00:07:54,360
has the filled-in square.

175
00:07:54,360 --> 00:07:56,700
The enzyme that catalyzed
this last reaction

176
00:07:56,700 --> 00:08:00,720
is HMG Coenzyme A
reductase, where HMG stands

177
00:08:00,720 --> 00:08:03,120
for hydroxymethylglutaryl.

178
00:08:03,120 --> 00:08:07,249
HMG CoA is a six-carbon
branch chain molecule.

179
00:08:07,249 --> 00:08:08,790
In the present
situation, we're going

180
00:08:08,790 --> 00:08:12,180
to look at HMG CoA as the
source of ketone bodies

181
00:08:12,180 --> 00:08:14,220
in the mitochondrion,
but I want you

182
00:08:14,220 --> 00:08:16,470
to keep in mind that
if this reaction were

183
00:08:16,470 --> 00:08:18,210
to occur not in
the mitochondrion

184
00:08:18,210 --> 00:08:21,660
but in the cytoplasm, the
resulting HMG CoA could

185
00:08:21,660 --> 00:08:23,310
be used for other pathways.

186
00:08:23,310 --> 00:08:26,070
For example, HMG
CoA in the cytosol

187
00:08:26,070 --> 00:08:28,455
is the precursor to cholesterol.

188
00:08:28,455 --> 00:08:30,330
With that in mind, let's
return our attention

189
00:08:30,330 --> 00:08:32,789
to the mitochondrion
and ketogenesis.

190
00:08:32,789 --> 00:08:35,970
The mitochondrial
enzyme HMG CoA lyase

191
00:08:35,970 --> 00:08:39,090
will split the HMG
CoA, knocking off

192
00:08:39,090 --> 00:08:42,210
an acetyl CoA in liberating
as the final product

193
00:08:42,210 --> 00:08:46,710
acetoacetate, which is our
first of three ketone bodies.

194
00:08:46,710 --> 00:08:49,560
Acetoacetate is a beta
keto acid and hence,

195
00:08:49,560 --> 00:08:52,250
prone to spontaneous
decarboxylation.

196
00:08:52,250 --> 00:08:55,440
Non enzymatically, this will
happen at some slow rate

197
00:08:55,440 --> 00:08:59,130
in order to liberate CO2
and produce acetone, which

198
00:08:59,130 --> 00:09:01,470
is our second ketone body.

199
00:09:01,470 --> 00:09:03,360
This acetone gives
the fruity smell

200
00:09:03,360 --> 00:09:05,580
to the breath of a diabetic
whose disease is out

201
00:09:05,580 --> 00:09:06,870
of control.

202
00:09:06,870 --> 00:09:09,810
Acetone is not going to be
biochemically useful to us,

203
00:09:09,810 --> 00:09:13,790
for example it's not going to be
metabolized to generate energy.

204
00:09:13,790 --> 00:09:16,210
The second chemical
fate of the acetoacetate

205
00:09:16,210 --> 00:09:20,770
is its reduction by NADH using
the enzyme beta hydroxybutyrate

206
00:09:20,770 --> 00:09:22,180
dehydrogenase.

207
00:09:22,180 --> 00:09:24,880
This reduction forms our
third ketone body beta

208
00:09:24,880 --> 00:09:28,780
hydroxybutyrate, which is a
biochemically useful molecule

209
00:09:28,780 --> 00:09:31,770
in that it serves as
a good metabolic fuel.

210
00:09:31,770 --> 00:09:34,420
Acetoacetate and
beta hydroxybutyrate

211
00:09:34,420 --> 00:09:37,210
do not need any kind
of special transporter

212
00:09:37,210 --> 00:09:39,530
to get out of the
cell into the blood.

213
00:09:39,530 --> 00:09:41,620
They diffuse through the
mitochondrial membrane

214
00:09:41,620 --> 00:09:43,810
and later through
the cell membrane.

215
00:09:43,810 --> 00:09:46,360
They are then transported
by the circulatory system

216
00:09:46,360 --> 00:09:49,300
from the liver to organs
that need them for energy.

217
00:09:49,300 --> 00:09:51,190
As you mentioned
above, ketone bodies

218
00:09:51,190 --> 00:09:53,920
are portable forms
of acetyl CoA.

219
00:09:53,920 --> 00:09:56,770
In a real sense, the liver
by making these ketone bodies

220
00:09:56,770 --> 00:09:59,050
is acting as a
food caterer where

221
00:09:59,050 --> 00:10:01,330
ketone bodies
represent food that's

222
00:10:01,330 --> 00:10:03,780
delivered to other organs.

223
00:10:03,780 --> 00:10:06,800
At this point let's
look at storyboard 24

224
00:10:06,800 --> 00:10:09,240
panel A. Now let's
take a look what

225
00:10:09,240 --> 00:10:11,850
happens when the ketone
bodies travel by the blood

226
00:10:11,850 --> 00:10:14,580
and are taken up by another
organ such as muscle.

227
00:10:14,580 --> 00:10:17,700
Acetoacetate, which I'll
refer to as ketone body

228
00:10:17,700 --> 00:10:20,220
one is good to go
and is ready to enter

229
00:10:20,220 --> 00:10:21,990
the main stream of metabolism.

230
00:10:21,990 --> 00:10:24,420
So I'm going to come
back to it in a minute.

231
00:10:24,420 --> 00:10:26,790
The beta hydroxybutyrate,
by contrast,

232
00:10:26,790 --> 00:10:28,830
has to be processed
in order for it

233
00:10:28,830 --> 00:10:32,250
to be useful to the target organ
skeletal muscle in this case.

234
00:10:32,250 --> 00:10:37,370
In step two, the muscle
form of beta hydroxybutyrate

235
00:10:37,370 --> 00:10:40,560
dehydrogenase will use
NAD plus to oxidize

236
00:10:40,560 --> 00:10:44,220
the beta hydroxybutyrate
into acetoacetate, which

237
00:10:44,220 --> 00:10:47,190
joins the pool of acetoacetate
that came in directly

238
00:10:47,190 --> 00:10:48,150
from the blood.

239
00:10:48,150 --> 00:10:52,380
We now have to put a thioester
group on the acetoacetate,

240
00:10:52,380 --> 00:10:54,840
and that comes from
an unusual source.

241
00:10:54,840 --> 00:10:58,470
In step three you'll see
a succinyl coenzyme A

242
00:10:58,470 --> 00:11:01,290
from the TCA cycle
giving its coenzyme

243
00:11:01,290 --> 00:11:04,440
A residue to acetoacetate,
which results

244
00:11:04,440 --> 00:11:08,100
in the formation of
acetoacetyl coenzyme A.

245
00:11:08,100 --> 00:11:11,340
This reaction happens in the
mitochondrion of the cell.

246
00:11:11,340 --> 00:11:14,790
At step four acetyl
coenzyme A is

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00:11:14,790 --> 00:11:18,690
converted by beta ketothiolase
into two molecules

248
00:11:18,690 --> 00:11:21,180
of acetyl coenzyme
A. And again, we're

249
00:11:21,180 --> 00:11:23,220
going to need another
coenzyme A group

250
00:11:23,220 --> 00:11:26,730
to come in at this point as
part of the beta ketothiolase

251
00:11:26,730 --> 00:11:28,140
reaction.

252
00:11:28,140 --> 00:11:30,240
Remember that beta
ketothiolase is

253
00:11:30,240 --> 00:11:32,730
the last enzyme that's
operative in beta oxidation

254
00:11:32,730 --> 00:11:34,230
of fatty acids.

255
00:11:34,230 --> 00:11:36,360
Here it's doing
the same chemistry

256
00:11:36,360 --> 00:11:37,980
that it does in beta oxidation.

257
00:11:37,980 --> 00:11:42,780
It splits acetoacetyl CoA
into two acetyl CoA molecules.

258
00:11:42,780 --> 00:11:44,880
And in steps five and
six, those molecules

259
00:11:44,880 --> 00:11:47,430
integrate into the TCA cycle.

260
00:11:47,430 --> 00:11:50,610
In the TCA cycle they're
oxidized to carbon dioxide

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00:11:50,610 --> 00:11:52,980
with the generation of energy.

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00:11:52,980 --> 00:11:55,080
Let me review for a
minute before going

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00:11:55,080 --> 00:11:58,290
into a physiological scenario.

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00:11:58,290 --> 00:12:00,540
Way over to the
left at step one,

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00:12:00,540 --> 00:12:03,600
the liver has made acetyl
CoA and packaged it

266
00:12:03,600 --> 00:12:06,560
into two ketone
bodies, acetoacetate

267
00:12:06,560 --> 00:12:08,640
and beta hydroxybutyrate.

268
00:12:08,640 --> 00:12:10,830
They travel in the
blood to target tissues,

269
00:12:10,830 --> 00:12:14,160
for example, the muscle,
or heart, or the brain.

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00:12:14,160 --> 00:12:17,790
In these target tissues these
ketone bodies are internalized,

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00:12:17,790 --> 00:12:22,380
converted to acetoacetate, and
then to acetoacetyl coenzyme A

272
00:12:22,380 --> 00:12:27,450
and then ultimately to several
molecules of acetyl coenzyme A.

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00:12:27,450 --> 00:12:30,360
The acetyl coenzyme A
that started in the liver,

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00:12:30,360 --> 00:12:33,240
ends up in the target
tissue and then can

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00:12:33,240 --> 00:12:35,260
be used to generate energy.

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00:12:35,260 --> 00:12:38,130
This is a particularly important
reaction under conditions

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00:12:38,130 --> 00:12:41,450
of starvation and diabetes.

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00:12:41,450 --> 00:12:45,590
Let's now look at panel
b of storyboard 24.

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00:12:45,590 --> 00:12:48,650
As you know, I like to look
at physiological scenarios

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00:12:48,650 --> 00:12:52,430
because at least to me, they
helped make biochemistry real.

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00:12:52,430 --> 00:12:55,355
The scenario I want to look
at is that of diabetes.

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00:12:55,355 --> 00:12:58,500
In Type 2 diabetes, which
is the type that I have,

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00:12:58,500 --> 00:13:02,390
my cells have become resistant
to taking up glucose.

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00:13:02,390 --> 00:13:04,910
My cells are
insulin insensitive.

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00:13:04,910 --> 00:13:07,880
After a meal I have very,
very high concentrations

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00:13:07,880 --> 00:13:11,150
of glucose in my blood,
because the cells of my tissues

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00:13:11,150 --> 00:13:13,670
are not capable of taking it in.

288
00:13:13,670 --> 00:13:17,000
Hence, if I do not take my
anti-diabetic medication

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00:13:17,000 --> 00:13:18,530
the sugar concentration
in my blood

290
00:13:18,530 --> 00:13:22,190
stays high, which leads to some
of the medical complications

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00:13:22,190 --> 00:13:23,090
of diabetes.

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00:13:23,090 --> 00:13:24,800
More on that later.

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00:13:24,800 --> 00:13:28,410
Given that there's a lot
of glucose in my blood,

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00:13:28,410 --> 00:13:30,290
but it's not getting
into my cells,

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00:13:30,290 --> 00:13:34,010
my cells are actually in a
technical state of starvation.

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00:13:34,010 --> 00:13:37,290
Take a look at the pathway
I've drawn in panel b.

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00:13:37,290 --> 00:13:40,270
Glucose on the left is
not getting into the cell.

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00:13:40,270 --> 00:13:43,020
I've used broken lines for
the pathway from glucose

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00:13:43,020 --> 00:13:46,590
to pyruvate and then from
pyruvate in the cytoplasm

300
00:13:46,590 --> 00:13:48,600
into the mitochondrial matrix.

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00:13:48,600 --> 00:13:51,870
These broken lines
are meant to indicate

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00:13:51,870 --> 00:13:54,960
that the pathways involved
are just not very active.

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00:13:54,960 --> 00:13:57,120
The sparse activity
of these pathways

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00:13:57,120 --> 00:13:59,700
means that acetyl CoA
levels are becoming somewhat

305
00:13:59,700 --> 00:14:01,520
limiting in the mitochondrion.

306
00:14:01,520 --> 00:14:03,930
Because pyruvate
is also limiting,

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00:14:03,930 --> 00:14:05,970
the enzyme pyruvate
carboxylase doesn't

308
00:14:05,970 --> 00:14:08,160
have sufficient
pyruvate in order

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00:14:08,160 --> 00:14:10,710
to maintain the
oxaloacetate concentration

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00:14:10,710 --> 00:14:13,240
within the mitochondrial matrix.

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00:14:13,240 --> 00:14:16,980
Once again, oxaloacetate is
the TCA cycle intermediate

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00:14:16,980 --> 00:14:20,860
that that's at the lowest, that
is micromolar concentration.

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00:14:20,860 --> 00:14:23,220
I'm focusing here on
the liver, although I

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00:14:23,220 --> 00:14:25,320
should add at this point
that all tissues are

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00:14:25,320 --> 00:14:27,840
similarly limited in
the pathways indicated

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00:14:27,840 --> 00:14:29,460
by the broken lines.

317
00:14:29,460 --> 00:14:31,890
The liver's response to
sensing this limitation

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00:14:31,890 --> 00:14:36,030
in carbohydrate processing
is to either take in lipid

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00:14:36,030 --> 00:14:38,460
or to break it down
from internal stores,

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00:14:38,460 --> 00:14:43,260
for example, triacylglycerides
in order to produce acetyl CoA.

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00:14:43,260 --> 00:14:45,870
But because oxaloacetate
is limiting,

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00:14:45,870 --> 00:14:48,420
the step at beta
ketothiolase backs up,

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00:14:48,420 --> 00:14:51,300
producing a large
amount of ketone bodies.

324
00:14:51,300 --> 00:14:53,910
The ketone bodies are
produced in excess,

325
00:14:53,910 --> 00:14:56,580
so you can see them escaping
into the mitochondrion

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00:14:56,580 --> 00:15:00,300
and later out of the cell, and
they go off into the blood.

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00:15:00,300 --> 00:15:02,700
Consequently, the
liver of diabetics

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00:15:02,700 --> 00:15:05,610
produces a lot of ketone
bodies, because it senses

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00:15:05,610 --> 00:15:08,710
that the body is starving,

330
00:15:08,710 --> 00:15:12,400
To the right of panel B, I have
some blood chemistry values

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00:15:12,400 --> 00:15:14,890
that are of relevance
to diabetics.

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00:15:14,890 --> 00:15:18,460
In a non-diabetic person,
blood sugar concentrations,

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00:15:18,460 --> 00:15:20,320
that is blood
glucose is maintained

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00:15:20,320 --> 00:15:22,540
at about 100
milligrams of glucose

335
00:15:22,540 --> 00:15:25,030
per 100 milliliters of blood.

336
00:15:25,030 --> 00:15:26,590
When I was diagnosed
with diabetes,

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00:15:26,590 --> 00:15:31,690
my blood sugar was over 300
milligrams per 100 milliliters.

338
00:15:31,690 --> 00:15:34,210
As I recall the symptoms
were disorientation.

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00:15:34,210 --> 00:15:36,730
I couldn't walk very
easily, I was thirsty,

340
00:15:36,730 --> 00:15:38,890
and I urinated a lot.

341
00:15:38,890 --> 00:15:41,050
Normal ketone body
concentrations

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00:15:41,050 --> 00:15:43,540
are less than 0.2 nanomolar.

343
00:15:43,540 --> 00:15:47,470
In a severe diabetic situation,
your ketone body concentrations

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00:15:47,470 --> 00:15:51,850
could be 15 to 25 millimolar
and the pH of your blood

345
00:15:51,850 --> 00:15:56,470
could drop from the mid 7
range down to about 6.8.

346
00:15:56,470 --> 00:15:59,710
The kidney responds to the
high concentration of glucose

347
00:15:59,710 --> 00:16:01,780
and the high
concentration of protons,

348
00:16:01,780 --> 00:16:06,700
that is the low pH, by
increasing urine volume output

349
00:16:06,700 --> 00:16:11,020
in order to try to urinate
out the glucose and protons.

350
00:16:11,020 --> 00:16:14,560
The results are that the
diabetic becomes excessively

351
00:16:14,560 --> 00:16:17,470
thirsty which again is
one of the biomarkers

352
00:16:17,470 --> 00:16:19,540
or symptoms of the disease.

353
00:16:19,540 --> 00:16:22,080
The classic historical
treatment of diabetes

354
00:16:22,080 --> 00:16:25,660
is to give insulin, which will
push more glucose into the cell

355
00:16:25,660 --> 00:16:28,960
and thus offset the biochemical
defect that leads ultimately

356
00:16:28,960 --> 00:16:31,810
to ketone bodies and to the
high concentration of glucose

357
00:16:31,810 --> 00:16:32,890
in the blood.

358
00:16:32,890 --> 00:16:35,230
Aside from giving
insulin by injection

359
00:16:35,230 --> 00:16:36,820
there are other
medications that will

360
00:16:36,820 --> 00:16:39,370
result in a sort of
reactivation of the beta cells

361
00:16:39,370 --> 00:16:42,640
in the pancreas in order to
produce more insulin naturally.

362
00:16:42,640 --> 00:16:45,040
Alternatively, there
are medications

363
00:16:45,040 --> 00:16:47,200
that will block
gluconeogenesis and thus

364
00:16:47,200 --> 00:16:50,350
stop the ability of the liver
and other gluconeogenic organs

365
00:16:50,350 --> 00:16:52,390
from producing glucose.

366
00:16:52,390 --> 00:16:55,090
So by blocking
gluconeogenesis, one

367
00:16:55,090 --> 00:16:57,910
can lower the glucose
concentration of the blood.

368
00:16:57,910 --> 00:17:01,930
As you see there are many, many
ways to treat this disease.

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00:17:01,930 --> 00:17:05,650
Let me add that it can be a very
debilitating disease, leading

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00:17:05,650 --> 00:17:09,880
to blindness, amputation, and
cardiovascular difficulties.

371
00:17:09,880 --> 00:17:12,130
It's a good idea to
try to avoid the risk

372
00:17:12,130 --> 00:17:14,230
factors for this disease.

373
00:17:14,230 --> 00:17:16,089
It's not fully
preventable at least

374
00:17:16,089 --> 00:17:19,300
in people who come from families
in which nearly everybody gets

375
00:17:19,300 --> 00:17:21,369
it, for example, my situation.

376
00:17:21,369 --> 00:17:24,490
But by avoiding risk factors you
can push off the date of onset

377
00:17:24,490 --> 00:17:26,417
by many years.